Inhibitors of serine proteases, particularly HCV NS3-NS4A protease

ABSTRACT

The present invention relates to compounds of formula I:  
                 
or a pharmaceutically acceptable salts thereof that inhibit serine protease activity, particularly the activity of hepatitis C virus NS3-NS4A protease. As such, they act by interfering with the life cycle of the hepatitis C virus and are useful as antiviral agents. The invention further relates to pharmaceutically acceptable compositions comprising said compounds either for ex vivo use or for administration to a patient suffering from HCV infection and to processes for preparing the compounds. The invention also relates to methods of treating an HCV infection in a patient by administering a pharmaceutical composition comprising a compound of this invention.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit, under 35 U.S.C. § 119, ofU.S. Provisional patent application No. 60/504,405, filed Sep. 18, 2003,entitled “Inhibitors of Serine Proteases, Particularly HCV NS3-NS4AProtease”, the entire contents of which is hereby incorporated byreference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds that inhibit serine proteaseactivity, particularly the activity of hepatitis C virus NS3-NS4Aprotease. As such, they act by interfering with the life cycle of thehepatitis C virus and are also useful as antiviral agents. The inventionfurther relates to pharmaceutical compositions comprising thesecompounds either for ex vivo use or for administration to a patientsuffering from HCV infection. The invention also relates to processesfor preparing the compounds and methods of treating an HCV infection ina patient by administering a pharmaceutical composition comprising acompound of this invention.

BACKGROUND OF THE INVENTION

Infection by hepatitis C virus (“HCV”) is a compelling human medicalproblem. HCV is recognized as the causative agent for most cases ofnon-A, non-B hepatitis, with an estimated human sero-prevalence of 3%globally [A. Alberti et al., “Natural History of Hepatitis C,” J.Hepatology, 31., (Suppl. 1), pp. 17-24 (1999)]. Nearly four millionindividuals may be infected in the United States alone [M. J. Alter etal., “The Epidemiology of Viral Hepatitis in the United States,Gastroenterol. Clin. North Am., 23, pp. 437-455 (1994); M. J. Alter“Hepatitis C Virus Infection in the United States,” J. Hepatology, 31.,(Suppl. 1), pp. 88-91 (1999)].

Upon first exposure to HCV only about 20% of infected individualsdevelop acute clinical hepatitis while others appear to resolve theinfection spontaneously. In almost 70% of instances, however, the virusestablishes a chronic infection that persists for decades [S. Iwarson,“The Natural Course of Chronic Hepatitis,” FEMS Microbiology Reviews,14, pp. 201-204 (1994); D. Lavanchy, “Global Surveillance and Control ofHepatitis C,” J. Viral Hepatitis, 6, pp. 35-47 (1999)]. This usuallyresults in recurrent and progressively worsening liver inflammation,which often leads to more severe disease states such as cirrhosis andhepatocellular carcinoma [M. C. Kew, “Hepatitis C and HepatocellularCarcinoma”, FEMS Microbiology Reviews, 14, pp. 211-220 (1994); I. Saitoet. al., “Hepatitis C Virus Infection is Associated with the Developmentof Hepatocellular Carcinoma,” Proc. Natl. Acad. Sci. USA, 87, pp.6547-6549 (1990)]. Unfortunately, there are no broadly effectivetreatments for the debilitating progression of chronic HCV.

The HCV genome encodes a polyprotein of 3010-3033 amino acids [Q. L.Choo, et. al., “Genetic Organization and Diversity of the Hepatitis CVirus.” Proc. Natl. Acad. Sci. USA, 88, pp. 2451-2455 (1991); N. Kato etal., “Molecular Cloning of the Human Hepatitis C Virus Genome FromJapanese Patients with Non-A, Non-B Hepatitis,” Proc. Natl. Acad. Sci.USA, 87, pp. 9524-9528 (1990); A. Takamizawa et. al., “Structure andOrganization of the Hepatitis C Virus Genome Isolated From HumanCarriers,” J. Virol., 65, pp. 1105-1113 (1991)]. The HCV nonstructural(NS) proteins are presumed to provide the essential catalytic machineryfor viral replication. The NS proteins are derived by proteolyticcleavage of the polyprotein [R. Bartenschlager et. al., “NonstructuralProtein 3 of the Hepatitis C Virus Encodes a Serine-Type ProteinaseRequired for Cleavage at the NS3/4 and NS4/5 Junctions,” J. Virol., 67,pp. 3835-3844 (1993); A. Grakoui et. al., “Characterization of theHepatitis C Virus-Encoded Serine Proteinase: Determination ofProteinase-Dependent Polyprotein Cleavage Sites,” J. Virol., 67, pp.2832-2843 (1993); A. Grakoui et. al., “Expression and Identification ofHepatitis C Virus Polyprotein Cleavage Products,” J. Virol., 67, pp.1385-1395 (1993); L. Tomei et. al., “NS3 is a serine protease requiredfor processing of hepatitis C virus polyprotein”, J. Virol., 67, pp.4017-4026 (1993)].

The HCV NS protein 3 (NS3) contains a serine protease activity thathelps process the majority of the viral enzymes, and is thus consideredessential for viral replication and infectivity. It is known thatmutations in the yellow fever virus NS3 protease decrease viralinfectivity [Chambers, T. J. et. al., “Evidence that the N-terminalDomain of Nonstructural Protein NS3 From Yellow Fever Virus is a SerineProtease Responsible for Site-Specific Cleavages in the ViralPolyprotein”, Proc. Natl. Acad. Sci. USA, 87, pp. 8898-8902 (1990)]. Thefirst 181 amino acids of NS3 (residues 1027-1207 of the viralpolyprotein) have been shown to contain the serine protease domain ofNS3 that processes all four downstream sites of the HCV polyprotein [C.Lin et al., “Hepatitis C Virus NS3 Serine Proteinase: Trans-CleavageRequirements and Processing Kinetics”, J. Virol., 68, pp. 8147-8157(1994)].

The HCV NS3 serine protease and its associated cofactor, NS4A, helpsprocess all of the viral enzymes, and is thus considered essential forviral replication. This processing appears to be analogous to thatcarried out by the human immunodeficiency virus aspartyl protease, whichis also involved in viral enzyme processing. HIV protease inhibitors,which inhibit viral protein processing, are potent antiviral agents inman, indicating that interrupting this stage of the viral life cycleresults in therapeutically active agents. Consequently HCV NS3 serineprotease is also an attractive target for drug discovery.

There are not currently any satisfactory anti-HCV agents or treatments.Until recently, the only established therapy for HCV disease wasinterferon treatment. However, interferons have significant side effects[M. A. Wlaker et al., “Hepatitis C Virus: An Overview of CurrentApproaches and Progress,” DDT, 4, pp. 518-29 (1999); D. Moradpour etal., “Current and Evolving Therapies for Hepatitis C,” Eur. J.Gastroenterol. Hepatol., 11, pp. 1199-1202 (1999); H. L. A. Janssen etal. “Suicide Associated with Alfa-Interferon Therapy for Chronic ViralHepatitis,” J. Hepatol., 21, pp. 241-243 (1994); P. F. Renault et al.,“Side Effects of Alpha Interferon,” Seminars in Liver Disease, 9, pp.273-277. (1989)] and induce long term remission in only a fraction (25%)of cases [O. Weiland, “Interferon Therapy in Chronic Hepatitis C VirusInfection”, FEMS Microbiol. Rev., 14, pp. 279-288 (1994)]. Recentintroductions of the pegylated forms of interferon (PEG-Intron® andPegasys®) and the combination therapy of ribavirin and pegylatedinterferon (Rebetrol®) have resulted in only modest improvements inremission rates and only partial reductions in side effects. Moreover,the prospects for effective anti-HCV vaccines remain uncertain.

Thus, there is a need for more effective anti-HCV therapies. Suchinhibitors would have therapeutic potential as protease inhibitors,particularly as serine protease inhibitors, and more particularly as HCVNS3 protease inhibitors. Specifically, such compounds may be useful asantiviral agents, particularly as anti-HCV agents.

SUMMARY OF THE INVENTION

The present invention addresses these needs by providing a compound offormula I:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

The invention also relates to compounds of formula I-1:

or pharmaceutically acceptable salts thereof, wherein the variables areas defined herein.

The invention also relates to compositions that comprise the abovecompounds and the use thereof. Such compositions may be used topre-treat invasive devices to be inserted into a patient, to treatbiological samples, such as blood, prior to administration to a patient,and for direct administration to a patient. In each case the compositionwill be used to inhibit HCV replication and to lessen the risk of or theseverity of HCV infection.

The invention also relates to processes for preparing the compounds offormula I.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a compound of formula I:

or a pharmaceutically acceptable salt thereof,wherein:

-   R₉ and R_(9′) are independently:    -   hydrogen-,    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C3-C10)-heterocyclyl-(C1-C12)aliphatic-,    -   (C5-C10)-heteroaryl-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;        -   wherein up to three aliphatic carbon atoms in each of R₉ and            R_(9′) may be replaced by O, N, NH, S, SO, or SO₂;        -   wherein each of R₉ and R_(9′) is independently and            optionally substituted with up to 3 substituents            independently selected from J;        -   J is halogen, —OR′, —NO₂, —CN, —CF₃, —OCF₃, —R′, oxo,            thioxo, ═N(R′), ═N(OR′), 1,2-methylenedioxy,            1,2-ethylenedioxy, —N(R′)₂, —SR′, —SOR′, —SO₂R′, —SO₂N(R′)₂,            —SO₃R′, —C(O)R′, —C(O)C(O)R′, —C(O)C(O)OR′, —C(O)C(O)N(R′)₂,            —C(O)CH₂C(O)R′, —C(S)R′, —C(S)OR′, —C(O)OR′, —OC(O)R′,            —C(O)N(R′)₂, —OC(O)N(R′)₂, —C(S)N(R′)₂, —(CH₂)₀₋₂NHC(O)R′,            —N(R′)N(R′)COR′, —N(R′)N(R′)C(O)OR′, —N(R′)N(R′)CON(R′)₂,            —N(R′)SO₂R′, —N(R′)SO₂N(R′)₂, —N(R′)C(O)OR′, —N(R′)C(O)R′,            —N(R′)C(S)R′, —N(R′)C(O)N(R′)₂, —N(R′)C(S)N(R′)₂,            —N(COR′)COR′, —N(OR′)R′, —C(═NH)N(R′)₂, —C(O)N(OR′)R′,            —C(═NOR′)R′, —OP(O)(OR′)₂, —P(O)(R′)₂, —P(O)(OR′)₂, or            —P(O)(H)(OR′); wherein;            -   R′ is independently selected from:            -   hydrogen-,            -   (C1-C12)-aliphatic-,            -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,            -   [(C3-C10)-cycloalkyl or                -cycloalkenyl]-(C1-C12)-aliphatic-,            -   (C6-C10)-aryl-,            -   (C6-C10)-aryl-(C1-C12)aliphatic-,            -   (C3-C10)-heterocyclyl-,            -   (C3-C10)-heterocyclyl-(C1-C12)aliphatic-,            -   (C5-C10)-heteroaryl-, or            -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;            -   wherein up to 5 atoms in R′ are optionally and                independently substituted with J;            -   wherein two R′ groups bound to the same atom optionally                form a 3- to 10-membered aromatic or non-aromatic ring                having up to 3 heteroatoms independently selected from                N, NH, O, S, SO, and SO₂, wherein said ring is                optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl,                (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, wherein                any ring has up to 3 substituents selected independently                from J;-   R₁₀, R_(10′), R₁₁, and R_(11′) are each independently:    -   hydrogen-,    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C3-C10)-heterocyclyl-(C1-C12)aliphatic-,    -   (C5-C10)-heteroaryl-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;        -   wherein any ring is optionally fused to a (C6-C10)aryl,            (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or            (C3-C10)heterocyclyl;        -   wherein up to 3 aliphatic carbon atoms in each of R₁₀,            R_(10′), R₁₁, and R_(11′) may be replaced by a heteroatom            selected from O, NH, S, SO, or SO₂ in a chemically stable            arrangement;        -   wherein each of R₁₀, R_(10′), R₁₁, and R_(11′) is            independently and optionally substituted with up to 3            substituents independently selected from J; or-   R₁₀ is —OR′ and R₁₀ is H; or-   R₁₀ and R_(10′) are both —OR′ or —SR′; or-   R₁₀ and R_(10′) are both fluorine; or-   R₁₀ and R_(10′) are taken together with the carbon atom to which    they are bound to form a 5- to 7-membered saturated or partially    unsaturated ring;    -   wherein the R₁₀ and R_(10′) atoms bound to the carbon atom are        independently C(H), N, NH, O, S, SO, or SO₂;    -   wherein said ring may contain up to 4 heteroatoms independently        selected from N, NH, O, S, SO, and SO₂;    -   wherein any atom is optionally singly or multiply substituted        with up to 2 substituents selected independently from J; and    -   wherein said ring is optionally fused to a second ring selected        from (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, and a        (C3-C10)heterocyclyl, wherein said second ring has up to 3        substituents selected independently from J; or-   R₉ and R₁₀ are taken together with the ring atoms to which they are    bound to form a 3- to 6-membered aromatic or non-aromatic ring    having up to 3 heteroatoms independently selected from N, NH, O, S,    SO, or SO₂; wherein said ring is optionally substituted with up to 3    substituents selected independently from J; or-   R₁₀ and R₁₁ are taken together with the ring atoms to which they are    bound to form a 3- to 6-membered aromatic or non-aromatic ring    having up to 3 heteroatoms independently selected from N, NH, O, S,    SO, or SO₂; wherein said ring is optionally substituted with up to 3    substituents selected independently from J; or-   R₉ and R₁₁ are taken together with the ring atoms to which they are    bound to form a bridged bicyclic saturated or partially unsaturated    carbocyclic or heterocyclic ring system containing up to 10 atoms;    wherein said ring system is optionally substituted with up to 3    substituents selected independently from J; wherein each heteroatom    in the heterocyclic ring system is selected from the group    consisting of N, NH, O, S, SO, or SO₂;-   R₁ and R₃ are independently:    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl- or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;        -   wherein up to 3 aliphatic carbon atoms in each of R₁ and R₃            may be replaced by a heteroatom selected from O, N, NH, S,            SO, or SO₂ in a chemically stable arrangement;        -   wherein each of R₁ and R₃ is independently and optionally            substituted with up to 3 substituents independently selected            from J;-   R₂, R₄, and R₇ are each independently:    -   hydrogen-,    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl-(C1-C12)-aliphatic-, or    -   (C6-C10)-aryl-(C1-C12)-aliphatic-;        -   wherein up to two aliphatic carbon atoms in each of R₂, R₄,            and R₇ may be replaced by a heteroatom selected from O, N,            NH, S, SO, and SO₂ in a chemically stable arrangement;        -   wherein each of R₂, R₄, and R₇ is optionally substituted            with up to 3 substituents independently selected from J;-   R₅ and R_(5′) are independently hydrogen or (C1-C12)-aliphatic,    wherein any hydrogen is optionally replaced with halogen; wherein    any terminal carbon atom of R₅ is optionally substituted with    sulfhydryl or hydroxy; or R₅ is Ph or —CH₂Ph and R_(5′) is H,    wherein said Ph or —CH₂Ph group is optionally substituted with up to    3 substituents independently selected from J; or-   R₅ and R_(5′) together with the atom to which they are bound    optionally form a 3- to 6-membered saturated or partially    unsaturated ring having up to 2 heteroatoms selected from N, NH, O,    SO, and SO₂; wherein said ring is optionally substituted with up to    2 substituents selected independently from J;-   W is:    -   wherein each R₆ is independently:        -   hydrogen-,        -   (C1-C12)-aliphatic-,        -   (C6-C10)-aryl-,        -   (C6-C10)-aryl-(C1-C12)aliphatic-,        -   (C3-C10)-cycloalkyl- or cycloalkenyl-,        -   [(C3-C10)-cycloalkyl- or cycloalkenyl]-(C1-C12)-aliphatic-,        -   (C3-C10)-heterocyclyl-,        -   (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-,        -   (C5-C10)-heteroaryl-, or        -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-,        -   wherein R₆ is optionally substituted with up to 3 J            substituents; or    -   two R₆ groups, together with the nitrogen atom to which they are        bound, optionally form a 3- to 10-membered aromatic or        non-aromatic ring having up to 3 heteroatoms independently        selected from N, NH, O, S, SO, and SO₂, wherein said ring is        optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl,        (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, wherein any ring        has up to 3 substituents selected independently from J;    -   wherein each R₈ is independently —OR′; or the R₈ groups together        with the boron atom, optionally form a (C3-C10)-membered        heterocyclic ring having in addition to the boron up to 3        additional heteroatoms selected from N, NR′, O, SO, and SO₂;-   X is —C(O)—, —S(O)—, or —S(O)₂—,-   V is —C(O)—, —S(O)—, —S(O)₂—, or —N(R₁₃)—;    -   wherein R₁₃ is:        -   hydrogen-,        -   (C1-C12)-aliphatic-,        -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,        -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,        -   (C6-C10)-aryl-,        -   (C6-C10)-aryl-(C1-C12)aliphatic-,        -   (C3-C10)-heterocyclyl-,        -   (C3-C10)-heterocyclyl-(C1-C12)aliphatic-,        -   (C5-C10)-heteroaryl-, or        -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;            -   wherein up to two aliphatic carbon atoms in R₁₃ may be                replaced by a heteroatom selected from O, N, NH, S, SO,                and SO₂ in a chemically stable arrangement;            -   wherein R₁₃ is independently and optionally substituted                with up to 3 substituents independently selected from J;-   R₁₂ and R_(12′) are independently:    -   hydrogen;    -   (C1-C12)-aliphatic-;    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-cycloalkyl or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-,    -   (C5-C10)-heteroaryl-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;        -   wherein up to 3 aliphatic carbon atoms in each of R₁₂ or            R_(12′) may be replaced by a heteroatom selected from O, N,            NH, S, SO, or SO₂ in a chemically stable arrangement;            -   wherein each of R₁₂ or R_(12′) is optionally substituted                with up to 3 substituents independently selected from J;                or-   R₁₂ and R_(12′) together with the nitrogen atom to which they are    bound, form a (C3-C10)-heterocyclic ring;    -   wherein said (C3-C10)-heterocyclic ring is optionally        substituted with up to 3 substituents independently selected        from J.

The present invention also provides a compound of formula I-1:

or a pharmaceutically acceptable salt thereof,wherein:

-   z is 0 or 1;-   R₉ and R_(9′) are independently:    -   hydrogen-,    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C3-C10)-heterocyclyl-(C1-C12)aliphatic-,    -   (C5-C10)-heteroaryl-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;        -   wherein up to three aliphatic carbon atoms in each of R₉ and            R_(9′), may be replaced by O, N, NH, S, SO, or SO₂;        -   wherein each of R₉ and R_(9′) is independently and            optionally substituted with up to 3 substituents            independently selected from J;        -   J is halogen, —OR′, —NO₂, —CN, —CF₃, —OCF₃, —R′, oxo,            thioxo, ═N(R′), ═N(OR′), 1,2-methylenedioxy,            1,2-ethylenedioxy, —N(R′)₂, —SR′, —SOR′, —SO₂R′, —SO₂N(R′)₂,            —SO₃R′, —C(O)R′, —C(O)C(O)R′, —C(O)C(O)OR′, —C(O)C(O)N(R′)₂,            —C(O)CH₂C(O)R′, —C(S)R′, —C(S)OR′, —C(O)OR′, —OC(O)R′,            —C(O)N(R′)₂, —OC(O)N(R′)₂, —C(S)N(R′)₂, —(CH₂)₀₋₂NHC(O)R′,            —N(R′)N(R′)COR′, —N(R′)N(R′)C(O)OR′, —N(R′)N(R′)CON(R′)₂,            —N(R′)SO₂R′, —N(R′)SO₂N(R′)₂, —N(R′)C(O)OR′, —N(R′)C(O)R′,            —N(R′)C(S)R′, —N(R′)C(O)N(R′)₂, —N(R′)C(S)N(R′)₂,            —N(COR′)COR′, —N(OR′)R′, —C(═NH)N(R′)₂, —C(O)N(OR′)R′,            —C(═NOR′)R′, —OP(O)(OR′)₂, —P(O)(R′)₂, —P(O)(OR′)₂, or            —P(O)(H)(OR′); wherein;            -   R′ is independently selected from:            -   hydrogen-,            -   (C1-C12)-aliphatic-,            -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,            -   [(C3-C10)-cycloalkyl or                -cycloalkenyl]-(C1-C12)-aliphatic-,            -   (C6-C10)-aryl-,            -   (C6-C10)-aryl-(C1-C12)aliphatic-,            -   (C3-C10)-heterocyclyl-,            -   (C3-C10)-heterocyclyl-(C1-C12)aliphatic-,            -   (C5-C10)-heteroaryl-, or            -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;            -   wherein up to 5 atoms in R′ are optionally and                independently substituted with J;            -   wherein two R′ groups bound to the same atom optionally                form a 3- to 10-membered aromatic or non-aromatic ring                having up to 3 heteroatoms independently selected from                N, NH, O, S, SO, and SO₂, wherein said ring is                optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl,                (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, wherein                any ring has up to 3 substituents selected independently                from J;-   R₁₀, R_(10′), R₁₁, and R_(11′) are each independently:    -   hydrogen-,    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C3-C10)-heterocyclyl-(C1-C12)aliphatic-,    -   (C5-C10)-heteroaryl-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;        -   wherein any ring is optionally fused to a (C6-C10)aryl,            (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or            (C3-C10)heterocyclyl;        -   wherein up to 3 aliphatic carbon atoms in each of R₁₀,            R_(10′), R₁₁, and R_(11′) may be replaced by a heteroatom            selected from O, NH, S, SO, or SO₂ in a chemically stable            arrangement;        -   wherein each of R₁₀, R_(10′), R₁₁, and R_(11′) is            independently and optionally substituted with up to 3            substituents independently selected from J; or-   R₁₀ is —OR′ and R_(10′) is H; or-   R₁₀ and R_(10′) are both —OR′ or —SR′; or-   R₁₀ and R_(10′) are both fluorine; or-   R₁₀ and R_(10′) are taken together with the carbon atom to which    they are bound to form a 5- to 7-membered saturated or partially    unsaturated ring;    -   wherein the R₁₀ and R_(10′) atoms bound to the carbon atom are        independently C(H), N, NH, O, S, SO, or SO₂;    -   wherein said ring may contain up to 4 heteroatoms independently        selected from N, NH, O, S, SO, and SO₂;    -   wherein any atom is optionally singly or multiply substituted        with up to 2 substituents selected independently from J; and    -   wherein said ring is optionally fused to a second ring selected        from (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, and a        (C3-C10)heterocyclyl, wherein said second ring has up to 3        substituents selected independently from J; or-   R₉ and R₁₀ are taken together with the ring atoms to which they are    bound to form a 3- to 6-membered aromatic or non-aromatic ring    having up to 3 heteroatoms independently selected from N, NH, O, S,    SO, or SO₂; wherein said ring is optionally substituted with up to 3    substituents selected independently from J; or-   R₁₀ and R₁₁ are taken together with the ring atoms to which they are    bound to form a 3- to 6-membered aromatic or non-aromatic ring    having up to 3 heteroatoms independently selected from N, NH, O, S,    SO, or SO₂; wherein said ring is optionally substituted with up to 3    substituents selected independently from J; or-   R₉ and R₁₁ are taken together with the ring atoms to which they are    bound to form a bridged bicyclic saturated or partially unsaturated    carbocyclic or heterocyclic ring system containing up to 10 atoms;    wherein said ring system is optionally substituted with up to 3    substituents selected independently from J; wherein each heteroatom    in the heterocyclic ring system is selected from the group    consisting of N, NH, O, S, SO, or SO₂;-   R₁ (if present) and R₃ are independently:    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl- or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;        -   wherein up to 3 aliphatic carbon atoms in each of R₁ (if            present) and R₃ may be replaced by a heteroatom selected            from O, N, NH, S, SO, or SO₂ in a chemically stable            arrangement;        -   wherein each of R₁ (if present) and R₃ is independently and            optionally substituted with up to 3 substituents            independently selected from J;-   R₂, R₄, and R₇ (if present) are each independently:    -   hydrogen-,    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl-(C1-C12)-aliphatic-, or    -   (C6-C10)-aryl-(C1-C12)-aliphatic-;        -   wherein up to two aliphatic carbon atoms in each of R₂, R₄,            and R₇ (if present) may be replaced by a heteroatom selected            from O, N, NH, S, SO, and SO₂ in a chemically stable            arrangement;        -   wherein each of R₂, R₄, and R₇ (if present) is optionally            substituted with up to 3 substituents independently selected            from J;-   R₅ and R_(5′) are independently hydrogen or (C1-C12)-aliphatic,    wherein any hydrogen is optionally replaced with halogen; wherein    any terminal carbon atom of R₅ is optionally substituted with    sulfhydryl or hydroxy; or R₅ is Ph or —CH₂Ph and R_(5′) is H,    wherein said Ph or —CH₂Ph group is optionally substituted with up to    3 substituents independently selected from J; or-   R₅ and R_(5′) together with the atom to which they are bound    optionally form a 3- to 6-membered saturated or partially    unsaturated ring having up to 2 heteroatoms selected from N, NH, O,    SO, and SO₂; wherein said ring is optionally substituted with up to    2 substituents selected independently from J;-   W is:    -   wherein    -   Y is —CO₂H, a derivative of —CO₂H, or a bioisostere of —CO₂H;    -   each R₆ is independently:        -   hydrogen-,        -   (C1-C12)-aliphatic-,        -   (C6-C10)-aryl-,        -   (C6-C10)-aryl-(C1-C12)aliphatic-,        -   (C3-C10)-cycloalkyl- or cycloalkenyl-,        -   [(C3-C10)-cycloalkyl- or cycloalkenyl]-(C1-C12)-aliphatic-,        -   (C3-C10)-heterocyclyl-,        -   (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-,        -   (C5-C10)-heteroaryl-, or        -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-,        -   wherein R₆ is optionally substituted with up to 3 J            substituents; or    -   two R₆ groups, together with the nitrogen atom to which they are        bound, optionally form a 3- to 10-membered aromatic or        non-aromatic ring having up to 3 heteroatoms independently        selected from N, NH, O, S, SO, and SO₂, wherein said ring is        optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl,        (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, wherein any ring        has up to 3 substituents selected independently from J;    -   wherein each R₈ is independently —OR′; or the R₈ groups together        with the boron atom, optionally form a (C3-C10)-membered        heterocyclic ring having in addition to the boron up to 3        additional heteroatoms selected from N, NR′, O, SO, and SO₂;-   X is —C(O)—, —S(O)—, or —S(O)₂—,-   V is —C(O)—, —S(O)—, —S(O)₂—, or —N(R₁₃)—;    -   wherein R₁₃ is:        -   hydrogen-,        -   (C1-C12)-aliphatic-,        -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,        -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,        -   (C6-C10)-aryl-,        -   (C6-C10)-aryl-(C1-C12)aliphatic-,        -   (C3-C10)-heterocyclyl-,        -   (C3-C10)-heterocyclyl-(C1-C12)aliphatic-,        -   (C5-C10)-heteroaryl-, or        -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;            -   wherein up to two aliphatic carbon atoms in R₁₃ may be                replaced by a heteroatom selected from O, N, NH, S, SO,                and SO₂ in a chemically stable arrangement;            -   wherein R₁₃ is independently and optionally substituted                with up to 3 substituents independently selected from J;-   R₁₂ and R_(12′) are independently:    -   hydrogen;    -   (C1-C12)-aliphatic-;    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-cycloalkyl or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-,    -   (C5-C10)-heteroaryl-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;        -   wherein up to 3 aliphatic carbon atoms in each of R₁₂ or            R_(12′) may be replaced by a heteroatom selected from O, N,            NH, S, SO, or SO₂ in a chemically stable arrangement;            -   wherein each of R₁₂ or R_(12′) is optionally substituted                with up to 3 substituents independently selected from J;                or-   R₁₂ and R_(12′) together with the nitrogen atom to which they are    bound, form a (C3-C10)-heterocyclic ring;    -   wherein said (C3-C10)-heterocyclic ring is optionally        substituted with up to 3 substituents independently selected        from J; and-   R₁₄ and R₁₅ are independently:    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl- or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C5-C10)-heteroaryl-(C1-C12)aliphatic-,        -   wherein up to 3 aliphatic carbon atoms in R₁₄ and R₁₅ may be            replaced by a heteroatom selected from O, N, NH, S, SO, or            SO₂ in a chemically stable arrangement;        -   wherein each of R₁₄ and R₁₅ is independently and optionally            substituted at each substitutable position with up to 3            substituents independently selected from J.            Definitions

The term “aryl” as used herein means a monocyclic or bicycliccarbocyclic aromatic ring system. Phenyl is an example of a monocyclicaromatic ring system. Bicyclic aromatic ring systems include systemswherein both rings are aromatic, e.g., naphthyl, and systems whereinonly one of the two rings is aromatic, e.g., tetralin. It is understoodthat as used herein, the term “(C6-C10)-aryl-” includes any one of a C6,C7, C8, C9, and C10 monocyclic or bicyclic carbocyclic aromatic ringsystem.

The term “bioisostere” —CO₂H as used in herein refers to a chemicalmoiety which may substitute for a carboxylic acid group in abiologically active molecule. Examples of such groups are disclosed inChristopher A. Lipinski, “Bioisosteres in Drug Design” Annual Reports inMedicinal Chemistry, 21, pp. 286-88 (1986), and in C. W. Thornber,“Isosterism and Molecular Modification in Drug Design” Chemical SocietyReviews, pp. 563-580 (1979). Examples of such groups include, but arenot limited to, —COCH₂OH, —CONHOH, SO₂NHR′, —SO₃H, —PO(OH)NH₂, —CONHCN,—OSO₃H, —CONHSO₂R′, —PO(OH)₂, —PO(OH)(OR′), —PO(OH)(R′), —OPO(OH)₂,—OPO(OH)(OR′), —OPO(OH)(R′), HNPO(OH)₂, —NHPO(OH) (OR′), —NHPO(OH) (R′)

The term “heterocyclyl” as used herein means a monocyclic or bicyclicnon-aromatic ring system having 1 to 3 heteroatom or heteroatom groupsin each ring selected from O, N, NH, S, SO, and SO₂ in a chemicallystable arrangement. In a bicyclic non-aromatic ring system embodiment of“heterocyclyl” one or both rings may contain said heteroatom orheteroatom groups. It is understood that as used herein, the term“(C5-C10)-heterocyclyl-” includes any one of a 5, 6, 7, 8, 9, and 10atom monocyclic or bicyclic non-aromatic ring system having 1 to 3heteroatoms or heteroatom groups in each ring selected from O, N, NH,and S in a chemically stable arrangement.

Examples of heterocyclic rings include 3-1H-benzimidazol-2-one,3-(1-alkyl)-benzimidazol-2-one, 2-tetrahydrofuranyl,3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino,3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl,3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl,1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl,1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl,2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, indolinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane,benzodithiane, and 1,3-dihydro-imidazol-2-one.

The term “heteroaryl” as used herein means a monocyclic or bicyclicaromatic ring system having 1 to 3 heteroatoms or heteroatom groups ineach ring selected from O, N, NH, and S in a chemically stablearrangement. In such a bicyclic aromatic ring system embodiment of“heteroaryl”:

-   -   one or both rings may be aromatic; and    -   one or both rings may contain said heteroatom or heteroatom        groups. It is understood that as used herein, the term        “(C5-C10)-heteroaryl-” includes any one of a 5, 6, 7, 8, 9, and        10 atom monocyclic or bicyclic aromatic ring system having 1 to        3 heteroatoms or heteroatom groups in each ring selected from O,        N, NH, and S in a chemically stable arrangement.

Examples of heteroaryl rings include 2-furanyl, 3-furanyl, N-imidazolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g.,3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g.,5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl,3-thienyl, benzofuryl, benzothiophenyl, indolyl (e.g., 2-indolyl),pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl,1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl,1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl,pyrazinyl, 1,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl,3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl,3-isoquinolinyl, or 4-isoquinolinyl).

The term “aliphatic” as used herein means a straight chained or branchedalkyl, alkenyl or alkynyl. It is understood that as used herein, theterm “(C1-C12)-aliphatic-” includes any one of a C1, C2, C3, C4, C5, C6,C7, C8, C9, C10, C11, and C12 straight or branched alkyl chain of carbonatoms. It is also understood that alkenyl or alkynyl embodiments need atleast two carbon atoms in the aliphatic chain. The term “cycloalkyl orcycloalkenyl” refers to a monocyclic or fused or bridged bicycliccarbocyclic ring system that is not aromatic. Cycloalkenyl rings haveone or more units of unsaturation. It is also understood that as usedherein, the term “(C3-C10)-cycloalkyl- or -cycloalkenyl-” includes anyone of a C3, C4, C5, C6, C7, C8, C9, and C10 monocyclic or fused orbridged bicyclic carbocyclic ring. Preferred cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,cycloheptyl, cycloheptenyl, nornbornyl, adamantyl and decalin-yl.

As used herein, the carbon atom designations may have the indicatedinteger and any intervening integer. For example, the number of carbonatoms in a (C1-C4)-alkyl group is 1, 2, 3, or 4. It should be understoodthat these designation refer to the total number of atoms in theappropriate group. For example, in a (C3-C10)-heterocyclyl the totalnumber of carbon atoms and heteroatoms is 3 (as in aziridine), 4, 5, 6(as in morpholine), 7, 8, 9, or 10.

The phrase “chemically stable arrangement” as used herein refers to acompound structure that renders the compound sufficiently stable toallow manufacture and administration to a mammal by methods known in theart. Typically, such compounds are stable at a temperature of 40° C. orless, in the absence of moisture or other chemically reactive condition,for at least a week.

EMBODIMENTS

According to one embodiment for compounds of formula I or formula I-1,the

radical is:

wherein:

-   R₁₂, R_(12′), and R₁₃ are as defined in any of the embodiments    herein.

According to another embodiment for compounds of formula I or formulaI-1, the

radical is:

wherein:

-   -   R_(12′) is hydrogen;    -   R₁₂ is:    -   (C1-C12)-aliphatic-;    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-cycloalkyl or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-,    -   (C5-C10)-heteroaryl-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;        -   wherein up to 3 aliphatic carbon atoms in R₁₂ may be            replaced by a heteroatom selected from O, N, NH, S, SO, or            SO₂ in a chemically stable arrangement;        -   wherein R₁₂ is optionally substituted with up to 3            substituents independently selected from J; and    -   R₁₃ is as defined in any of the embodiments herein.

According to another embodiment for compounds of formula I or formulaI-1, the

radical is:

wherein:

-   -   R_(12′) is hydrogen;

-   R₁₂ is:    -   (C1-C12)-aliphatic-;    -   (C6-C10)-aryl-(C1-C12) aliphatic-, or    -   (C3-C10)-cycloalkyl or -cycloalkenyl-;        -   wherein up to 3 aliphatic carbon atoms in R₁₂ may be            replaced by a heteroatom selected from O, N, NH, S, SO, or            SO₂ in a chemically stable arrangement;        -   wherein R₁₂ is optionally substituted with up to 3            substituents independently selected from J; and    -   R₁₃ is as defined in any of the embodiments herein.

According to another embodiment for compounds of formula I or formulaI-1, the

radical is:

wherein:

-   -   R_(12′) is hydrogen; and    -   R₁₂ is:    -   (C1-C12)-aliphatic-;    -   (C6-C10)-aryl-(C1-C12) aliphatic-, or    -   (C3-C10)-cycloalkyl or -cycloalkenyl-;        -   wherein up to 3 aliphatic carbon atoms in R₁₂ may be            replaced by a heteroatom selected from O, N, NH, S, SO, or            SO₂ in a chemically stable arrangement; and        -   wherein R₁₂ is optionally substituted with up to 3            substituents independently selected from J.

According to another embodiment for compounds of formula I and formulaI-1, the

radical is;

-   -   In another embodiment for compounds of formula I or formula I-1,        the        radical is;

According to another embodiment, the present invention provides acompound of formula IA:

wherein:

-   -   R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R₉, R_(9′), R₁₀, R_(10′), R₁₁,        R_(11′), R₁₂, z, and W are as defined in any of the embodiments        herein.

According to one embodiment for compounds of formula IA, z is one, W isselected from:

and R₆ and R₈ are as defined in any of the embodiments herein.

According to another embodiment for compounds of formula IA, z is 0, Wis selected from:

and R₁₄ and R₁₅ are as defined in any of the embodiments herein.

According to another embodiment for compounds of formula I or formulaI-1, the

radical is:

wherein:

-   -   R₁₂, and R_(12′) are as defined in any of the embodiments        herein.

According to another embodiment for compounds of formula I or formulaI-1, the

radical is:

wherein:

-   -   R_(12′) is hydrogen; and    -   R₁₂ is:    -   (C1-C12)-aliphatic-;    -   (C6-C10)-aryl-(C1-C12)aliphatic-, or    -   (C3-C10)-cycloalkyl or -cycloalkenyl-;        -   wherein up to 3 aliphatic carbon atoms in R₁₂ may be            replaced by a heteroatom selected from O, N, NH, S, SO, or            SO₂ in a chemically stable arrangement; and        -   wherein R₁₂ is optionally substituted with up to 3            substituents independently selected from J.

In certain embodiments of formula I, wherein z is 1 and the

radical is attached to N(R₇), R₇ is hydrogen.

In certain embodiments of formula I-1, wherein z is 1 and the

radical is attached to N(R₇), R₇ is hydrogen.

In certain other embodiments for compounds of formula I-1, wherein z is0 and the

radical is attached to N(R₂), R₂ is hydrogen.

According to another embodiment for compounds of formula I or formulaI-1, the

radical is:

wherein:

-   -   n is 0, 1, or 2;    -   Z and Z′ are independently C(H), N, NH, O, or S;    -   R₉, R_(9′), R₁₁, and R_(11′) are as defined in any of the        embodiments herein; and    -   the spirocyclic ring containing Z and Z′ is optionally        substituted with up to 3 J substituents, wherein J is as defined        in any of the embodiments herein.

According to another embodiment for compounds of formula I or I-1, the

radical is:

wherein:

-   -   R₁₁ and R_(11′) are both H;    -   n is 0, 1, or 2;    -   R₉ and R_(9′) are as defined in any of the embodiments herein;        and    -   the spirocyclic ring containing Z and Z′ is optionally        substituted with up to 3 J substituents, wherein J is as defined        in any of the embodiments herein.

According to another embodiment for compounds of formula I or I-1, the

radical is:

wherein:

-   -   n is 0 or 1.

According to another embodiment, the present invention provides acompound of formula IB:

wherein:

-   -   R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R₉, R_(9′), R₁₁, R_(11′), R₁₂,        z, Z, Z′, n, and W are as defined in any of the embodiments        herein.

According to another embodiment, the present invention provides acompound of formula IB-1:

wherein:

-   -   R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R₉, R_(9′), R₁₁, R_(11′), R₁₂,        R_(12′), X, V, n, z, Z, Z′, and W are as defined in any of the        embodiments herein.

According to one embodiment for compounds of formula IB or formula IB-1,z is one, W is selected from:

and R₆ and R₈ are as defined in any of the embodiments herein.

According to another embodiment for compounds of formula IB or formulaIB-1, z is 0, W is selected from:

and R₁₄ and R₁₅ are as defined in any of the embodiments herein.

According to another embodiment for compounds of formula I or formulaI-1, the

radical is:

wherein:

-   -   Z and Z′ are independently C(H), N, NH, O, or S;    -   R₉, R_(9′), R₁₁, and R_(11′) are as defined in any of the        embodiments herein; and    -   the fused benzo ring is optionally substituted with up to 3 J        substituents, wherein J is as defined in any of the embodiments        herein.

According to another embodiment, the present invention provides acompound of formula IC:

wherein:

-   -   R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R₉, R_(9′), R₁₁, R_(11′), R₁₂,        z, Z, Z′, and W are as defined in any of the embodiments herein;        and    -   the fused benzo ring is optionally substituted with up to 3 J        substituents, wherein J is as defined in any of the embodiments        herein.

According to another embodiment for compounds of formula IC, z is 1, Zand Z′ are S, R₉, R_(9′), R₁₁, and R_(11′), are H, R₁, R₂, R₃, R₄, R₅,R_(5′), R₇, R₁₂, and W are as defined in any of the embodiments hereinand the fused benzo ring is optionally substituted with up to 3 Jsubstituents, wherein J is as defined in any of the embodiments herein.

In another embodiment for compounds of formula IC, z is 0, Z and Z′ areS, R₉, R_(9′), R₁₁, and R_(11′) are H, R₁, R₂, R₃, R₄, R₅, R_(5′), R₇,R₁₂, and W are as defined in any of the embodiments herein and the fusedbenzo ring is optionally substituted with up to 3 J substituents,wherein J is as defined in any of the embodiments herein.

According to another embodiment, the present invention provides acompound of formula IC-1:

wherein:

-   -   R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R₉, R_(9′), R₁₁, R_(11′), R₁₂,        R_(12′), X, V, z, Z, Z′ and W are as defined in any of the        embodiments herein; and    -   the fused benzo ring is optionally substituted with up to 3 J        substituents, wherein J is as defined in any of the embodiments        herein.

According to another embodiment for compounds of formula IC-1, z is 1, Zand Z′ are S, R₉, R_(9′), R₁₁, and R_(11′) are H, R₁, R₂, R₃, R₄, R₅,R_(5′), R₇, R₁₂, R_(12′), X, V, and W are as defined in any of theembodiments herein and the fused benzo ring is optionally substitutedwith up to 3 J substituents, wherein J is as defined in any of theembodiments herein.

In another embodiment for compounds of formula IC-1, z is 0, Z and Z′are S, R₉, R_(9′), R₁₁, and R_(11′) are H, R₁, R₂, R₃, R₄, R₅, R_(5′),R₇, R₁₂, R_(12′), X, V, and W are as defined in any of the embodimentsherein and the fused benzo ring is optionally substituted with up to 3 Jsubstituents, wherein J is as defined in any of the embodiments herein.

According to yet another embodiment for compounds of formula IC orformula IC-1, z is one, W is selected from:

and R₆ and R₈ are as defined in any of the embodiments herein.

According to still another embodiment for compounds of formula IC orformula IC-1, z is 0, W is selected from:

and R₁₄ and R₁₅ are as defined in any of the embodiments herein.

According to another embodiment for compounds of formula I or formulaI-1, the

radical is:

wherein:

-   -   R₉, R_(9′), R₁₁, and R_(11′) are H; and    -   R′ is selected from:    -   hydrogen-,    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C3-C10)-heterocyclyl-(C1-C12)aliphatic-,    -   (C5-C10)-heteroaryl-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;    -   wherein up to 5 atoms in R′ are optionally and independently        substituted with J;

According to another embodiment for compounds of formula I or formulaI-1, the

radical is:

wherein:

-   -   R₉, R_(9′), R₁₁, and R_(11′) are H.

In yet another embodiment for compounds of formula I or formula I-1, the

radical is:

wherein:

-   R₉, R_(9′), R₁₁, and R_(11′), are H.

According to another embodiment, the present invention provides acompound of formula ID:

wherein:

-   -   R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R₉, R_(9′), R₁₁, R_(11′), R₁₂,        z, and W are as defined in any of the embodiments herein.

According to another embodiment, the present invention provides acompound of formula ID-1:

wherein:

-   -   R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R₉, R_(9′), R₁₁, R_(11′), R₁₂,        R_(12′), X, V, z, and W are as defined in any of the embodiments        herein.

According to one embodiment for compounds of formula ID or formula ID-1,z is 1.

According to another embodiment for compounds of formula ID or formulaID-1, z is 0.

According to yet another embodiment for compounds of formula ID orformula ID-1, z is one, W is selected from:

and R₆ and R₈ are as defined in any of the embodiments herein.

According to another embodiment for compounds of formula ID or formulaID-1, z is 0, w is selected from:

and R₁₄ and R₁₅ are as defined in any of the embodiments herein.

According to another embodiment for compounds of formula I or formulaI-1, in the

radical,

-   -   R₉, R₁₀, R_(10′), R₁₁, and R_(11′) are H; and    -   R_(9′) is:    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   (C6-C10)-aryl-,    -   (C3-C10)-heterocyclyl-, or    -   (C5-C10)-heteroaryl-;    -   wherein up to three aliphatic carbon atoms in R_(9′) may be        replaced by O, N, NH, S, SO, or SO₂;    -   wherein R_(9′) is independently and optionally substituted with        up to 3 substituents independently selected from J.

According to another embodiment for compounds of formula I or formulaI-1, the

radical is:

According to another embodiment for compounds of formula I or formulaI-1, in the

radical

-   -   R₉, R_(9′), R₁₀, R₁₁, and R_(11′) are H; and    -   R_(10′) is:    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   (C6-C10)-aryl-,    -   wherein any ring is optionally fused to a (C6-C10)aryl,        (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl;    -   wherein up to 3 aliphatic carbon atoms in R_(10′) may be        replaced by a heteroatom selected from O, NH, S, SO, or SO₂ in a        chemically stable arrangement;    -   wherein R_(10′), is independently and optionally substituted        with up to 3 substituents independently selected from J.

According to another embodiment for compounds of formula I or formulaI-1, the

radical is:

wherein the R_(10′) group, is independently and optionally substitutedwith up to 3 substituents independently selected from J.

According to yet another embodiment for compounds of formula I orformula I-1, in the

radical

-   -   R₉, R_(9′), R₁₀, R_(10′), and R₁₁ are H; and    -   R_(11′) is:    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   (C6-C10)-aryl-,    -   wherein any ring is optionally fused to a (C6-C10)aryl,        (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl;    -   wherein up to 3 aliphatic carbon atoms in R₁₁, may be replaced        by a heteroatom selected from O, NH, S, SO, or SO₂ in a        chemically stable arrangement;    -   wherein R_(11′), is independently and optionally substituted        with up to 3 substituents independently selected from J.

According to another embodiment for compounds of formula I or formulaI-1, the

radical is:

According to another embodiment for compounds of formula I or formulaI-1, in the

radical

-   -   R₉, R₁₀, R₁₁, and R_(11′) are H; and    -   R₉, and R_(10′) are:    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   wherein up to 3 aliphatic carbon atoms in R_(9′) and R_(10′) may        be replaced by a heteroatom selected from O, NH, S, SO, or SO₂        in a chemically stable arrangement;    -   wherein R_(9′) and R_(10′) are independently and optionally        substituted with up to 3 substituents independently selected        from J.

According to another embodiment for compounds of formula I or formulaI-1, the

radical is:

According to another embodiment for compounds of formula I or formulaI-1, in the

radical

-   -   R₉, R_(9′), R_(10′), R₁₁, and R_(11′) are H; and    -   R′ is selected from:    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C3-C10)-heterocyclyl-(C1-C12)aliphatic-,    -   (C5-C10)-heteroaryl-, and    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;    -   wherein up to 5 atoms in R′ are optionally and independently        substituted with J.

According to another embodiment for compounds of formula I or formulaI-1, the

radical is:

-   -   wherein up to 5 atoms in R′ are optionally and independently        substituted with J.

According to another embodiment for compounds of formula I or formulaI-1, the

radical is:

wherein up to 5 atoms in R′ are optionally and independently substitutedwith J.

According to another embodiment for compounds of formula I or formulaI-1, the radical is:

According to yet another embodiment for compounds of formula I orformula I-1, in the

radical

-   -   R₉, R_(9′), R_(10′), R₁₁, and R_(11′) are H; and    -   R′ is selected from:    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-heterocyclyl-(C1-C12)aliphatic-, and    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;        -   wherein up to 5 atoms in R′ are optionally and independently            substituted with J.

According to another embodiment for compounds of formula I or formulaI-1, the

radical is:

-   -   wherein up to 5 atoms in R′ are optionally and independently        substituted with J.

According to another embodiment, the present invention provides acompound of formula IE:

wherein:

-   -   R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R₉, R_(9′), R_(10′), R′, R₁₁,        R_(11′), R₁₂, z, and W are as defined in any of the embodiments        herein.

According to another embodiment, the present invention provides acompound of formula IE-1:

wherein:

-   -   R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R₉, R_(9′), R_(10′), R′, R₁₁,        R_(11′). R₁₂, R_(12′), z, X, V, and W are as defined in any of        the embodiments herein.

According to one embodiment for compounds of formula IE or formula IE-1,z is 1.

According to another embodiment for compounds of formula IE or formulaIE-1, z is 0.

According to yet another embodiment for compounds of formula IE orformula IE-1, z is one, W is selected from:

and R₆ and R₈ are as defined in any of the embodiments herein.

According to another embodiment for compounds of formula IE or formulaIE-1, z is 0, W is selected from:

and R₁₄ and R₁₅ are as defined in any of the embodiments herein.

According to another embodiment for compounds of formula I or formulaI-1, the

radical is:

wherein;

-   -   ring A is a 5- to 6-membered aromatic or 3- to 6-membered        non-aromatic ring having up to 3 heteroatoms independently        selected from N, NH, O, SO, or SO₂;    -   wherein said ring A is optionally fused to a (C6-C10)aryl,        (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl;    -   wherein any ring has up to 3 substituents selected independently        from J; and    -   R₉, R_(9′), R_(10′), and R_(11′) are as defined in any of the        embodiments herein.

According to another embodiment for compounds of formula I or formulaI-1, the

radical is:

According to another embodiment for compounds of formula I or formulaI-1, the

radical is:

According to another embodiment for compounds of formula I or formulaI-1, the

radical is:

According to yet another embodiment for compounds of formula I orformula I-1, the

radical is:

According to another embodiment, the present invention provides acompound of formula IF:

wherein:

-   -   R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R₉, R_(9′), R_(10′), R_(11′),        R₁₂, z, W, and ring A are as defined in any of the embodiments        herein.

According to another embodiment, the present invention provides acompound of formula IF-1:

wherein:

-   -   R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R₉, R_(9′), R₁₀, R_(11′), R₁₂,        R_(12′), z, X, V, W, and ring A are as defined in any of the        embodiments herein.

According to another embodiment, the present invention provides acompound of formula IF-2:

wherein:

-   -   R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, z, X, V, and W, are as defined        in any of the embodiments herein.

According to one embodiment of compounds of formula IF, formula IF-1, orformula IF-2, z is 1.

According to another embodiment of compounds of formula IF, formulaIF-1, or formula IF-2, z is 0.

According to one embodiment for compounds of formula IF, formula IF-1,or formula IF-2, z is 1, w is selected from:

and R₆ and R₈ are as defined in any of the embodiments herein.

According to another embodiment for compounds of formula IF, formulaIF-1, or formula IF-2, z is 0, W is selected from:

and R₁₄ and R₁₅ are as defined in any of the embodiments herein.

According to another embodiment for compounds of formula I or formulaI-1, the

radical is:

wherein;

-   -   ring A is a 5- to 6-membered aromatic or 3- to 6-membered        non-aromatic ring having up to 3 heteroatoms independently        selected from N, NH, O, SO, or SO₂;    -   wherein said ring A is optionally fused to a (C6-C10)aryl,        (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl;    -   wherein any ring has up to 3 substituents selected independently        from J; and    -   R_(9′), R_(10′), R₁₁, and R_(11′) are as defined in any of the        embodiments herein.        According to another embodiment for compounds of formula I or        formula I-1, the        radical is:

According to yet another embodiment for compounds of formula I orformula I-1, the

radical is:

According to another embodiment, the present invention provides acompound of formula IG:

wherein:

-   -   R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R_(9′), R_(10′), R_(11′), R₁₂,        z, W. and ring A are as defined in any of the embodiments        herein.

According to another embodiment, the present invention provides acompound of formula IG-1:

wherein:

-   -   R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R_(9′), R_(10′), R_(11′), R₁₂,        R_(12′), Z, W. X, V, and ring A are as defined in any of the        embodiments herein.

According to one embodiment for compounds of formula IG or formula IG-1,z is 1.

According to another embodiment of compounds of formula IG or formulaIG-1, z is 0.

According to yet another embodiment for compounds of formula IG orformula IG-1, z is one, W is selected from:

and R₆ and R₈ are as defined in any of the embodiments herein.

According to still another embodiment for compounds of formula IG orformula IG-1, z is 0, w is selected from:

and R₁₄ and R₁₅ are as defined in any of the embodiments herein.

According to another embodiment for compounds of formula I or formulaI-1, the

radical is:

wherein:

-   -   ring B forms a 3- to a 20-membered carbocyclic or heterocyclic        ring system;    -   wherein each ring B is either aromatic or nonaromatic;    -   wherein each heteroatom in the heterocyclic ring system is N,        NH, O, SO, or SO₂;    -   wherein ring B is optionally fused to a (C6-C10)aryl,        (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl;    -   wherein each ring has up to 3 substituents selected        independently from J; and        R_(9′) and R_(11′) are as defined in any of the embodiments        herein.

According to another embodiment for compounds of formula I or formulaI-1, the

radical is:

According to yet another embodiment, the present invention provides acompound of formula IH:

wherein:

-   -   R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R_(9′), R_(11′), R₁₂, z, W, and        ring B are as defined in any of the embodiments herein.

According to yet another embodiment, the present invention provides acompound of formula 1H-1:

wherein:

-   -   R₁, R₂, R₃, R₄, R₅, R_(5′), R₇, R_(9′), R_(11′), R₁₂, R_(12′),        z, X, V, W, and ring B are as defined in any of the embodiments        herein.

According to one embodiment for compounds of formula IH and formula1H-1, z is 1.

According to another embodiment for compounds of formula IH and formula1H-1, z is 0.

According to yet another embodiment for compounds of formula IH orformula 1H-1, z is one, W is selected from:

and R₆ and R₈ are as defined in any of the embodiments herein.

According to another embodiment for compounds of formula IH or formula1H-1, z is 0, W is selected from:

and R₁₄ and R₁₅ are as defined in any of the embodiments herein.

According to another embodiment, W in compounds of formula I or formulaI-1 is:

wherein in the W, the NR₆R₆ is selected from —NH—(C1-C6 aliphatic),—NH—(C3-C6 cycloalkyl), —NH—CH(CH₃)-aryl, or —NH—CH(CH₃)-heteroaryl,wherein said aryl or said heteroaryl is optionally substituted with upto 3 halogens.

According to another embodiment for compounds of formula I or formulaI-1, the NR₆R₆ in the W radical is:

According to another embodiment for compounds of formula I or formulaI-1, the NR₆R₆ in the W radical is:

In another embodiment of compounds of formula I or formula I-1, in theW, the NR₆R₆ is:

In yet another embodiment for compounds of formula I or formula I-1, inthe W, the NR₆R₆ is:

According to another embodiment for compounds of formula I or formulaI-1, the NR₆R₆ in the W radical is:

According to another embodiment in compounds of formula I or formulaI-1, the NR₆R₆ in the W radical is:

In yet another embodiment for compounds of formula I or formula I-1, inthe W, the NR₆R₆ is:

According to another embodiment, the present invention provides acompound of formula IJ:

wherein:

-   -   z, R₁, R₂, R₃, R₄, R₅, R_(5′), R₆, R₇, R₉, R_(9′), R₁₀, R_(10′),        R₁₁, R_(11′), and R₁₂, are as defined in any of the embodiments        herein.

According to another embodiment, the present invention provides acompound of formula IJ-1:

wherein:

-   -   R₁, R₂, R₃, R₄, R₅, R_(5′), R₆, R₇, R₉, R_(9′), R₁₀, R_(10′),        R₁₁, R_(11′), R_(11′), R₁₂, z, X, and V are as defined in any of        the embodiments herein.

According to one embodiment for compounds of formula IJ and formulaIJ-1, z is 1.

According to another embodiment, W in compounds of formula I or formulaI-1 is:

wherein R₈ is as defined above.

According to another embodiment for W in compounds of formula I orformula I-1, each R₈ together with the boron atom, is a(C5-C10)-membered heterocyclic ring having no additional heteroatomsother than the boron and the two oxygen atoms. In one embodiment, theheterocyclic ring is:

-   -   wherein R′ is (C1-C6)-aliphatic. In another embodiment, R′ is        methyl.

According to another embodiment, when W in compounds of formula I orformula I-1 is:

wherein R₈ is as defined above, then z is 1.

According to another embodiment, W in compounds of formula I or formulaI-1 is:

wherein R₆ is as defined in any of the embodiments herein.

According to another embodiment, when W in compounds of formula I orformula I-1 is:

wherein R₆ is as defined in any of the embodiments herein, then z is 1.

According to yet another embodiment, W in compounds of formula I orformula I-1 is:

wherein R₆ is as defined in any of the embodiments herein.

According to another embodiment, when W in compounds of formula I orformula I-1 is:

wherein R₆ is as defined in any of the embodiments herein, then z is 1.

According to another embodiment, W in compounds of formula I or formulaI-1 is:

wherein R₆ is as defined in any of the embodiments herein.

According to another embodiment, when W in compounds of formula I orformula I-1 is:

wherein R₆ is hydrogen, then z is 1.

According to another embodiment, the present invention provides acompound of formula Ij:

wherein:

-   -   R₁, R₂, R₃, R₄, R₅, R_(5′), R₆, R₇, R₉, R_(9′), R₁₀, R_(10′),        R₁₁, R_(11′), R_(12′), R₁₂, and z are as defined in any of the        embodiments herein.

According to one embodiment for compounds of formula Ij, z is 1.

According to another embodiment for compounds of formula Ij, R₅, andR_(5′) are:

According to another embodiment for compounds of formula Ij, R₅, andR_(5′) are:

According to another embodiment for compounds of formula I or formulaI-1, R_(5′) is hydrogen and R₅ is:

According to another embodiment for compounds of formula I or formulaI-1, R_(5′) is hydrogen and R₅ is:

According to another embodiment, the present invention provides acompound of formula IK:

wherein:

-   -   z, R₁, R₂, R₃, R₄, R₆, R₇, R₉, R_(9′), R₁₀, R_(10′), R₁₁,        R_(11′), and R₁₂, are as defined in any of the embodiments        herein.

According to another embodiment, the present invention provides acompound of formula IK-1:

wherein:

-   -   R₁, R₂, R₃, R₄, R₆, R₇, R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′),        R_(12′), R₁₂, z, X, and V are as defined in any of the        embodiments herein.

According to another embodiment for compounds of formula IK or formulaIK-1, R₁, R₂, R₃, R₄, R₆, R₇, R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′),R_(12′), R₁₂, X, and V are as defined in any of the embodiments herein,z is 1, and NR₆R₆ is:

According to another embodiment for compounds of formula IK or formulaIK-1, R₁, R₂, R₃, R₄, R₆, R₇, R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′),R_(12′), R₁₂, X, and V are as defined in any of the embodiments hereinand z is 1.

According to another embodiment, the present invention provides acompound of formula IK-2:

wherein:

-   -   R₁, R₂, R₃, R₄, R₇, R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′),        R_(12′), R₁₂, z, X, V, and W are as defined in any of the        embodiments herein.

According to another embodiment for compounds of formula IK-2, z is 1, Wis selected from:

and R₆ and R₈ are as defined in any of the embodiments herein.

According to another embodiment for compounds of formula IK-2, z is 0, Wis selected from:

and R₁₄ and R₁₅ are as defined in any of the embodiments herein.

According to another embodiment for compounds of formula I or formulaI-1, R_(5′) and R₅ are:

According to another embodiment for compounds of formula I or formulaI-1, R₇ if present, and R₂, R₄, and R_(12′) are each independently H,methyl, ethyl, or propyl.

According to another embodiment for compounds of formula I or formulaI-1, R₇ if present, and R₂ and R₄ are each H.

According to another embodiment, the present invention provides acompound of formula IL:

wherein:

-   -   z, R₁, R₃, R₆, R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′), and R₁₂        are as defined in any of the embodiments herein.

According to another embodiment, the present invention provides acompound of formula IL-1:

wherein:

-   -   R₁, R₃, R₆, R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′), R_(12′),        R₁₂, z, X, and V are as defined in any of the embodiments        herein.

According to one embodiment for compounds of formula IL or formula IL-1,R₁, R₃, R₆, R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′), R_(12′), R₁₂, z, X,and V are as defined in any of the embodiments herein, and NR₆R₆ is:

According to another embodiment for compounds of formula IL or formulaIL-1, z is one, R₁, R₃, R₆, R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′),R_(12′), R₁₂, X, and V are as defined in any of the embodiments herein,and NR₆R₆ is:

According to another embodiment, the present invention provides acompound of formula IL-2:

wherein:

-   -   R₁, R₃, R₅, R_(5′), R₆, R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′),        R_(12′), R₁₂, z, X, V, and W are as defined in any of the        embodiments herein.

According to another embodiment for compounds of formula IL-2, z is one,W is selected from:

and R₆ and R₈ are as defined in any of the embodiments herein.

According to another embodiment for compounds of formula IL-2, z is 0, Wis selected from:

and R₁₄ and R₁₅ are as defined in any of the embodiments herein.

According to another embodiment for compounds of formula I or formulaI-1, R₃ is:

According to another embodiment for compounds of formula I or formulaI-1, R₃ is:

According to yet another embodiment for compounds of formula I orformula I-1, R₃ is:

According to another embodiment, the present invention provides acompound of formula IM:

wherein:

-   -   z is 1, and R₁, R₆, R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′), and        R₁₂ are as defined in any of the embodiments herein.

According to another embodiment, the present invention provides acompound of formula IM-1:

wherein:

-   -   z is 1, and R₁, R₆, R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′), R₁₂,        R_(12′), X, and V are as defined in any of the embodiments        herein.

According to another embodiment, the present invention provides acompound of formula IM-2:

wherein:

-   -   R₁, R₅, R_(5′), R₆, R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′), R₁₂,        R_(12′), z, X, V, and W are as defined in any of the embodiments        herein.

According to another embodiment, the present invention provides acompound of formula IM-3:

wherein:

-   -   R₁, R₂, R₄, R₅, R_(5′), R₆, R₇, R₉, R_(9′), R₁₀, R_(10′), R₁₁,        R_(11′), R₁₂, R_(12′), z, X, V, and W are as defined in any of        the embodiments herein.

According to another embodiment for compounds of formula IM-2 or formulaIM-3, z is one, W is selected from:

and R₆ and R₈ are as defined in any of the embodiments herein.

According to another embodiment for compounds of formula IM-2 or formulaIM-3, z is 0, W is selected from:

and R₁₄ and R₁₅ are as defined in any of the embodiments herein.

According to another embodiment for compounds of formula I or formulaI-1, R₁ is:

According to another embodiment for compounds of formula I or formulaI-1, R₁ is:

In yet another embodiment for compounds of formula I or formula I-1, R₁is cyclohexyl.

According to another embodiment, the present invention provides acompound of formula IN:

wherein:

-   -   R₆, R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′), and R₁₂ are as        defined in any of the embodiments herein.

According to another embodiment, the present invention provides acompound of formula IN-1:

wherein:

-   -   R₆, R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′), R_(12′), R₁₂, X and        V are as defined in any of the embodiments herein.

According to another embodiment for compounds of formula IN, and formulaIN-1, R₆, R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′), R_(12′), R₁₂, X and Vare as defined in any of the embodiments herein, and NR₆R₆ is:

According to another embodiment, the present invention provides acompound of formula IN-2:

wherein:

-   -   R₃, R₅, R_(5′), R₆, R₉, R_(9′), R₁₀, R_(10′), R₁₁, R_(11′),        R_(12′), R₁₂, X V, and W are as defined in any of the        embodiments herein.

According to another embodiment, the present invention provides acompound of formula IN-3:

wherein:

-   -   R₂, R₃, R₄, R₅, R_(5′), R₆, R₇, R₉, R_(9′), R₁₀, R_(10′), R₁₁,        R_(11′), R_(12′), R₁₂, X, V, and W are as defined in any of the        embodiments herein.

According to another embodiment for compounds of formula IN-2 or formulaIN-3, z is one, W is selected from:

and R₆ and R₈ are as defined in any of the embodiments herein.

According to another embodiment for compounds of formula IN-2 or formulaIN-3, z is 0, W is selected from:

and R₁₄ and R₁₅ are as defined in any of the embodiments herein.

According to another embodiment for compounds of formula I or formulaI-1, optional J substituents on any substitutable nitrogen are selectedfrom —R′, —N(R′)₂, —N(R′)SO₂R′, —SO₂R′, —SO₂N(R′)₂, —C(O)R′, —C(O)OR′,—C(O)C(O)R′, —C(O)C(O)N(R′)₂, —C(O)CH₂C(O)R′, —C(═NH)N(R′)₂, or—C(O)N(R′)₂.

According to another embodiment for compounds of formula I or formulaI-1, no carbon atoms of R₁, R₃, R₅, and R_(5′) are replaced with N. NH,O, or S. In other embodiments of compounds of formula I or I-1, theseR₁, R₃, R₅, and R_(5′) groups have no J substituents.

According to another embodiment for compounds of formula I, the compoundis:

The compounds of this invention may contain one or more asymmetriccarbon atoms and thus may occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. All such isomeric forms of these compounds are expresslyincluded in the present invention. Each stereogenic carbon may be of theR or S configuration.

In one embodiment, the compounds of this invention have the structureand stereochemistry depicted in compounds 1-12.

Any of the embodiments recited herein, including those embodiments inthe above species, may define formula I or formula I-1 individually orbe combined to produce an embodiment of this invention.

Abbreviations which are used in the schemes, preparations and theexamples that follow are:

-   THF: tetrahydrofuran-   DMF: N,N,-dimethylformamide-   EtOAc: ethyl acetate-   AcOH: acetic acid-   NMM: N-methylmorpholine-   NMP: N-methylpyyrolidinone-   EtOH: ethanol-   t-BuOH: tert-butanol-   Et₂O: diethyl ether-   DMSO: dimethyl sulfoxide-   DCCA: dichloroacetic acid-   DIEA: diisopropylethylamine-   MeCN: acetonitrile-   TFA: trifluoroacetic acid-   DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene-   DEAD: diethyl azodicarboxylate-   HOBt: 1-hydroxybenzotriazole hydrate-   HOAt: 1-hydroxy-7-azabenzotriazole-   EDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-   Boc: tert-butyloxycarbonyl-   Boc₂O: di-tert-butyldicarbonate-   Cbz: benzyloxycarbonyl-   Cbz-Cl: benzyl chloroformate-   Fmoc: 9-fluorenyl methyloxycarbonyl-   Chg: cyclohexylglycine-   t-BG: tert-butylglycine-   mCBPA: 3-chloroperoxybenzoic acid-   DAST: (diethylamino)sulfur trifluoride-   TEMPO: 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical-   PyBOP: tris(pyrrolidino)bromophosphonium hexafluorophosphate-   TBTU or HATU: 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium    tetrafluoroborate-   DMAP: 4-dimethylaminopyridine-   AIBN: 2,2′-azobisisobutyronitrile-   DMEM: Dulbecco's minimal essential media-   PBS: phosphate-buffered saline-   rt or RT: room temperature-   ON: overnight-   ND: not determined-   MS: mass spectrometry-   LC: liquid chromatography    General Synthetic Methodology:

The compounds of this invention may be prepared in general by methodsknown to those skilled in the art. Schemes 1-16 below illustratesynthetic routes to the compounds of the present invention. Otherequivalent schemes, which will be readily apparent to the ordinaryskilled organic chemist, may alternatively be used to synthesize variousportions of the molecule as illustrated by the general schemes below,and the preparative examples that follow.

Scheme 1 above provides a general route for the preparation of compoundsof formula I, II, IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK, IL, IN, and INwherein X-V is —C(O)C(O), W is —C(O)C(O)—N(R₆)₂, R², R⁴, and R⁷ are H,and R¹, R³, R⁵, R^(5′), R⁹, R^(9′), R¹⁰, R^(10′), R¹¹, R^(11′), R¹², andR^(12′) are as described in any of the embodiments herein. As would berecognized by skilled practitioners, other suitable and commerciallyavailable coupling reagents may be used to prepare intermediates 15, 17,19, and 22. Additionally, it will be recognized that the commerciallyavailable Cbz protected amino acids represented by, for instance,Cbz-P3-OH, may alternatively be substituted with the commercial t-Bocprotected amino acids. Suitable deprotection conditions to remove theBoc protecting groups are known to those skilled in the art. Likewisethe oxidation of intermediate 22 to compounds of formula II may beaccomplished using other suitable conditions known to the skilledartisan.

Scheme 2 above provides a general route for the preparation of compoundsof formula 26. Therein, commercially available amine 23 and sulfonylchloride 24 are condensed and then hydrolyzed under basic conditions toprovide intermediate acid 26. Alternatively, the skilled practitionerwill recognize that other suitable reagents may be used to prepareintermediate 26.

Scheme 3 above provides a general route for the preparation of compoundsof formula III and formula I. Therein, coupling of the acid 26 and amine20 to give amide intermediate 27 may be accomplished using theconditions indicated or coupling reagents known to one of skill in theart. Subsequent oxidation of keto alcohol 27 with Dess Martinperiodinane, or other oxidation conditions known to those skilled in theart, affords compounds of formula III or formula I, wherein X-V is—C(O)S(O)₁₋₂, W is —C(O)C(O)—N(R₆)₂, R², R⁴, and R⁷ are H, and R¹, R³,R⁵, R^(5′), R⁹, R^(9′), R¹⁰, R^(10′), R¹¹, R^(11′), R¹², and R^(12′) areas described in any of the embodiments herein.

Scheme 4 above provides a general route for the preparation of compoundsof formula VI and formula I. Therein, compound 28 is prepared accordingto the methods described in Kessler et al., J. Med. Chem., pp. 1918-1930(2003). Addition of the Fmoc-oxadiazolone in an appropriate solventgives semi-carbazide 29. Deprotection of the Fmoc group with piperidinein N-methylpyrrolidinone followed by oxidation with Dess Martinperiodinane gives compounds of formula IV. It will be appreciated bythose skilled in the art that other known conditions can be used toaccomplish the oxidation of compounds 29 to compounds of formula I andIV.

Scheme 5 above provides a general route for the preparation of compoundsof formula V and formula I. Therein, commercially available amino acidester 30 is converted to the corresponding N-chlorosulfonyl ester 31according to the procedure described by Kempf, D. J. et al., J. Med.Chem., pp. 320-330 (1993). Coupling of 31 with commercially availablehydrazine 32 followed by hydrolysis yields acid 34. Coupling of the acid34 and amine 18 to give amide intermediate 35 may be accomplished usingthe conditions indicated or coupling reagents known to one of skill inthe art. Subsequent oxidation of 35 with Dess Martin periodinane, orother suitable conditions known to those skilled in the art, affordscompounds of formula V and formula I.

Scheme 6 above provides a general route for the preparation of compoundsof formula I and formula VI, wherein X-V is —S(O)₁₋₂C(O)—, W is—C(O)C(O)—N(R₆)₂, R², R⁴, and R⁷ are H, and R¹, R³, R⁵, R^(5′), R⁹,R^(9′), R¹⁰, R^(10′), R¹¹, R^(11′), R¹², and R^(12′) are as described inany of the embodiments herein. Chloroester 37 is prepared according tothe methods described in J. Org. Chem., pp. 2624-2629 (1979). Couplingof commercially available amino t-butyl ester 36 with chloride 37 givessulfonamide 38. Basic hydrolysis of mixed ester 38 followed by couplingwith commercially available amine 39 affords intermediate ester 40.Oxidation with one equivalent of mCBPA affords sulfoxide 41, wherein Xis —S(O)₁—. Alternatively, oxidation with two equivalents of mCBPAaffords sulfone 41, wherein X is —S(O)₂—. Acidic hydrolysis of t-butylester 40 yields acid 41, which is coupled to amine 18 (describedpreviously in Scheme 1) to give keto alcohol 42. Finally, oxidation of42 with Dess Martin periodinane or other suitable conditions know in theart gives compounds of formula VI.

Scheme 7 above provides a general route for the preparation of compoundsof formula IB-1, formula IB, and formula IC, wherein X-V is —C(O)C(O)—,W is —C(O)C(O)—N(R₆)₂, R², R⁴, and R⁷ are H, and n, Z, Z′, R¹, R³, R⁵,R^(5′), R⁹, R^(9′), R¹⁰, R^(10′), R¹¹, R^(11′), R¹², and R^(12′) are asdescribed in any of the embodiments herein. As would be recognized byskilled practitioners, other suitable and commercially availablecoupling reagents may be used to prepare intermediates 47, 49, 51, and53. Additionally, it will be recognized that the commercially availableBoc protected amino acids represented by, for instance, Boc-P3-OH, mayalternatively be substituted with the commercial CBz protected aminoacids. Suitable deprotection conditions to remove the Cbz protectinggroups are known to those skilled in the art. Likewise the oxidation ofintermediate 53 to compounds of formula IB-1 may be accomplished usingother suitable conditions known to the skilled artisan.

Scheme 8 above provides a general route for the preparation of compoundsof formula ID-1 and formula ID, wherein X-V is —C(O)C(O)—, W is—C(O)C(O)—N(R₆)₂, R², R⁴, and R⁷ are H, and R¹, R³, R⁵, R^(5′), R⁶, R¹²,and R^(12′) are as described in any of the embodiments herein. As wouldbe recognized by any skilled practitioner, other suitable andcommercially available coupling reagents may be used to prepareintermediates 56, 58, 60, and 62. Additionally, it will be recognizedthat the commercially available Boc protected amino acids representedby, for instance, Boc-P3-OH, may alternatively be substituted with thecommercial CBz protected amino acids. Suitable deprotection conditionsto remove the Cbz protecting groups are known to those skilled in theart. Likewise, the oxidation of intermediate 62 to compounds of formulaID-1 may be accomplished using other suitable conditions known to theskilled artisan.

Scheme 9 above provides a general route for the preparation of compoundsof formula IE-1 and formula IE, wherein X-V is —C(O)C(O)—, W is—C(O)C(O)—N(R₆)₂, R²R⁴, and R⁷ are H, and R′, R¹, R³, R⁵, R^(5′), R⁶,R¹² and R^(12′) are as described in any of the embodiments herein. Thesteps used in scheme 9 could be modified by, for example, usingdifferent reagents or carrying out the reactions in a different order.As would be recognized by any skilled practitioner, other suitable andcommercially available coupling reagents may be used to prepareintermediates 66, 67, 69, and 70. Additionally, it will be recognizedthat the commercially available Cbz protected amino acids representedby, for instance, Cbz-P3-OH, may alternatively be substituted with thecommercial t-Boc protected amino acids. Suitable deprotection conditionsto remove the Boc protecting groups are known to those skilled in theart. Likewise, the oxidation of intermediate 70 to compounds of formulaIE-1 may be accomplished using other suitable conditions known to theskilled artisan.

Scheme 10 above, depicts an alternative approach to preparing compoundsof formulae IE-1 and IE of this invention wherein, X-V is —C(O)C(O)—, Wis —C(O)C(O)—N(R₆)₂, R², R⁴, and R⁷ are H, and R′, R¹, R³, R⁵, R^(5′),R⁶, R¹², and R^(12′) are as described in any of the embodiments herein.In this approach, a 4-hydroxyproline derivative 71 is reacted with acommercially available R′-halide (such an aryl chloride), represented byR′—X, in the presence of a suitable base (such as potassium t-butoxide)to provide a compound 72. As would be appreciated by any skilledpractitioner, the compound 72 then may be carried on to compounds offormula IE-1 by routine methods. Additionally, other suitable andcommercially available coupling reagents may be used to prepareintermediates 74, 75, 76, and 77. Furthermore, it will be recognizedthat the commercially available Boc protected amino acids representedby, for instance, Boc-P3-OH, may alternatively be substituted with thecommercial CBz protected amino acids. Suitable deprotection conditionsto remove the Cbz protecting groups are known to those skilled in theart. Likewise, the oxidation of intermediate 77 to compounds of formulaIE-1 may be accomplished using other suitable conditions known to theskilled artisan.

Scheme 11 above provides a general route for the preparation ofcompounds of formula IF-1 and formula IF, wherein X-V is —C(O)C(O)—, Wis —C(O)C(O)—N(R₆)₂, R², R⁴, and R⁷ are H, and ring A, R¹, R³, R⁵,R^(5′), R⁶, R¹², and R^(12′) are as described in any of the embodimentsherein. The steps used in scheme 11 could be modified by, for example,using different reagents or carrying out the reactions in a differentorder. As would be recognized by any skilled practitioner, othersuitable and commercially available coupling reagents may be used toprepare intermediates 79, 80, 81, and 82. Additionally, it will berecognized that the commercially available Cbz protected amino acidsrepresented by, for instance, Cbz-P3-OH, may alternatively besubstituted with the commercial t-Boc protected amino acids. Suitabledeprotection conditions to remove the Boc protecting groups are known tothose skilled in the art. Likewise, the oxidation of intermediate 82 tocompounds of formula IF-1 may be accomplished using other suitableconditions known to the skilled artisan.

Scheme 12 above provides a synthetic route for the preparation ofcompound 84. Scheme 12 could be modified using techniques known toskilled practitioners to arrive at compound 84. Additionally, othercommercially available oxalamide esters may be converted into thecorresponding acids by a route analogous to that described above.

Scheme 13 provides a synthetic route for the preparation ofnon-commercially available oxalamide esters or oxalamide acids ofinterest. Scheme 13 may be modified using techniques known to skilledpractitioners to arrive at compounds represented by formula 88.

Scheme 14 above provides a synthetic route for the preparation ofcompound 1 from 89 (BOC-protected octahydro-indole-2-carboxylic acid).Intermediate 89 may be prepared from commercially availableoctahydro-indole-2-carboxylic acid (Bachem) according to the proceduredescribed in PCT publication No. WO 03/087092 (the entire of contents ofwhich is hereby incorporated by reference) and references cited therein.Scheme 14 could be modified using techniques known to skilledpractitioners to arrive at compound 1. The experimental procedures toprepare compound 1 are further exemplified below in Example 2.

Scheme 15 above provides a synthetic route for the preparation ofCbz-protected azabicyclo[2.2.1]heptane-3-carboxylic acid, compound 99and the corresponding t-butyl ester, compound 100. The free acid 99 maybe further elaborated by the route defined in scheme 1 above to preparecompounds of formulae I and IH. Alternatively, the t-butyl ester 100 maybe further elaborated by a modification of schemes 9 or 10 above to givecompounds of formulae I and IH.

Scheme 16 above provides a general route for the preparation ofcompounds of formula IP and formula I-1, wherein R⁵ is H, R^(5′) isn-propyl, W is —C(O)C(O)—NH—C(R₁₄)—C(O)—NH—C(R₁₅)—Y, R², R⁴, and R⁷ areH, and ring A, X, V, R¹, R³, R⁵, R^(5′), R⁶, R⁹, R^(9′), R¹⁰, R^(10′),R¹¹, R^(11′), R¹⁴, R¹⁵, Y, z, R¹², and R^(12′) are as described in anyof the embodiments herein. The steps used in scheme 16 could be modifiedby, for example, using different reagents or carrying out the reactionsin a different order. As would be recognized by any skilledpractitioner, other suitable and commercially available couplingreagents may be used to prepare intermediates 103, 106, and 108.Additionally, it will be recognized that the commercially available Cbzprotected amino acids represented by, for instance, Cbz-R₁₄—COOH, mayalternatively be substituted with the commercial t-Boc protected aminoacids. Suitable deprotection conditions to remove the Boc protectinggroups are known to those skilled in the art. Likewise, the oxidation ofintermediate 108 to compounds of formula IP may be accomplished usingother suitable conditions known to the skilled artisan. Intermediateacid 105 was prepared according to the procedure described by Harbeson,S. et al., J. Med. Chem., Vol. 37, No. 18, pp. 2918-2929 (1994).

The preparation of various other optionally substituted multicyclicazaheterocyclyl intermediates to prepare compounds of formulae I and IGvia schemes 1, 9 or 10 above, may be accomplished by the methodsdescribed in PCT publication No. WO 02/18369 (the entire of contents ofwhich is hereby incorporated by reference) and references cited therein.

Various 3, 4, and 5-substituted proline analogues may either bepurchased commercially or prepared according to known literatureprocedures. For instance, for compounds of formula I wherein R_(9′) is(C1-C12)-aliphatic-, the starting 3-substituted proline analogues may beprepared according to the method of Holladay, M. W. et al., J. Med.Chem., 34, pp. 457-461 (1991). For compounds of formula I wherein eitherR_(9′), R_(10′), or R_(11′) are cyclohexyl and R₉, R₁₀, or R₁₁ arehydrogen, the cyclohexyl proline intermediates may be prepared byplatinum oxide reduction of the commercially available phenylsubstituted proline analogues. Such reduction conditions are well knownto those skilled in the art. For compounds of formula I wherein R_(9′)is (C1-C12)-aliphatic- and R_(10′) is (C1-C12)-aliphatic-, the starting3,4-disubstituted proline analogues may be prepared according to themethod of Kanamasa, S. et al., J. Org. Chem, 56, pp. 2875-2883 (1991).In each of the syntheses involving 3, 4, or 5-substituted prolines or3,4-disubstituted prolines, the intermediates may be further elaboratedby the routes defined above in schemes 1, 9, or 10 to prepare compoundsof formula I.

Accordingly, one embodiment of this invention provides a process forpreparing a compound of formula I, as defined in any of the embodimentsherein, comprising the step of: reacting a compound of formula VII inthe presence of a compound of formula VIII to provide a compound offormula IX:

wherein:

-   R₁₇ is an amine protecting group, a P3-residue of an HCV protease    inhibitor described herein, or a P4-P3-residue of an HCV protease    inhibitor as described herein, and wherein the P3 and the P4-P3    residues are optionally substituted with an amino-terminal capping    group;-   R₁₆ is a carboxy protecting group or a P1 residue of an HCV protease    inhibitor described herein, wherein the P1 residue is optionally    substituted with a carboxy terminal protecting group or with W. R′    is as defined in any of the embodiments herein. X is an appropriate    leaving group. As would be appreciated by skilled practitioners, an    appropriate leaving group may be generated in situ.

In an alternative embodiment, the 4-hydroxy group in formula VII may beconverted to a leaving group. In such an embodiment, X is a nucleophilicoxygen which reacts with VII to provide IX.

As used herein, P1, P3, P4 refer to the residues of an HCV proteaseinhibitor as defined in the art and as are well known to skilledpractitioners.

The compound of formula IX may be carried on to a compound of formula Iaccording to the methods described herein.

Although certain embodiments are depicted and described below, it willbe appreciated that compounds of this invention can be preparedaccording to the methods described generally above using appropriatestarting materials generally available to one of ordinary skill in theart.

Another embodiment of this invention provides a pharmaceuticalcomposition comprising a compound of formula I or formula I-1 orpharmaceutically acceptable salts thereof. According to anotherembodiment, the compound of formula I or formula I-1 is present in anamount effective to decrease the viral load in a sample or in a patient,wherein said virus encodes a serine protease necessary for the virallife cycle, and a pharmaceutically acceptable carrier.

If pharmaceutically acceptable salts of the compounds of this inventionare utilized in these compositions, those salts are preferably derivedfrom inorganic or organic acids and bases. Included among such acidsalts are the following: acetate, adipate, alginate, aspartate,benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate,camphor sulfonate, cyclopentane-propionate, digluconate, dodecylsulfate,ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate,pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.Base salts include ammonium salts, alkali metal salts, such as sodiumand potassium salts, alkaline earth metal salts, such as calcium andmagnesium salts, salts with organic bases, such as dicyclohexylaminesalts, N-methyl-D-glucamine, and salts with amino acids such asarginine, lysine, and so forth.

Also, the basic nitrogen-containing groups may be quaternized with suchagents as lower alkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides and iodides; dialkyl sulfates, such as dimethyl,diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkylhalides, such as benzyl and phenethyl bromides and others. Water oroil-soluble or dispersible products are thereby obtained.

The compounds utilized in the compositions and methods of this inventionmay also be modified by appending appropriate functionalities to enhanceselective biological properties. Such modifications are known in the artand include those which increase biological penetration into a givenbiological system (e.g., blood, lymphatic system, central nervoussystem), increase oral availability, increase solubility to allowadministration by injection, alter metabolism and alter rate ofexcretion.

Pharmaceutically acceptable carriers that may be used in thesecompositions include, but are not limited to, ion exchangers, alumina,aluminum stearate, lecithin, serum proteins, such as human serumalbumin, buffer substances such as phosphates, glycine, sorbic acid,potassium sorbate, partial glyceride mixtures of saturated vegetablefatty acids, water, salts or electrolytes, such as protamine sulfate,disodium hydrogen phosphate, potassium hydrogen phosphate, sodiumchloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

According to another embodiment, the compositions of this invention areformulated for pharmaceutical administration to a mammal. In oneembodiment said mammal is a human being.

Such pharmaceutical compositions of the present invention may beadministered orally, parenterally, by inhalation spray, topically,rectally, nasally, buccally, vaginally or via an implanted reservoir.The term “parenteral” as used herein includes subcutaneous, intravenous,intramuscular, intra-articular, intra-synovial, intrasternal,intrathecal, intrahepatic, intralesional and intracranial injection orinfusion techniques. In another embodiment, the compositions areadministered orally or intravenously.

Sterile injectable forms of the compositions of this invention may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such ascarboxymethyl cellulose or similar dispersing agents which are commonlyused in the formulation of pharmaceutically acceptable dosage formsincluding emulsions and suspensions. Other commonly used surfactants,such as Tweens, Spans and other emulsifying agents or bioavailabilityenhancers which are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation.

In one embodiment, dosage levels of between about 0.01 and about 100mg/kg body weight per day of the protease inhibitor compounds describedherein are useful in a monotherapy for the prevention and treatment ofantiviral, particularly anti-HCV mediated disease. In anotherembodiment, dosage levels of between about 0.5 and about 75 mg/kg bodyweight per day of the protease inhibitor compounds described herein areuseful in a monotherapy for the prevention and treatment of antiviral,particularly anti-HCV mediated disease. Typically, the pharmaceuticalcompositions of this invention will be administered from about 1 toabout 5 times per day or alternatively, as a continuous infusion. Suchadministration can be used as a chronic or acute therapy. The amount ofactive ingredient that may be combined with the carrier materials toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. A typical preparation willcontain from about 5% to about 95% active compound (w/w). In oneembodiment, such preparations contain from about 20% to about 80% activecompound.

When the compositions of this invention comprise a combination of acompound of formula I or formula I-1 and one or more additionaltherapeutic or prophylactic agents, both the compound and the additionalagent should be present at dosage levels of between about 10 to 100% ofthe dosage normally administered in a monotherapy regimen. In anotherembodiment, the additional agent should be present at dosage levels ofbetween about 10 to 80% of the dosage normally administered in amonotherapy regimen.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers that are commonly used includelactose and corn starch. Lubricating agents, such as magnesium stearate,are also typically added. For oral administration in a capsule form,useful diluents include lactose and dried cornstarch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions of this invention may beadministered in the form of suppositories for rectal administration.These may be prepared by mixing the agent with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract may be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions may be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith our without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

In one embodiment, the pharmaceutical compositions are formulated fororal administration.

In another embodiment, the compositions of this invention additionallycomprise another anti-viral agent, preferably an anti-HCV agent. Suchanti-viral agents include, but are not limited to, immunomodulatoryagents, such as α-, β-, and γ-interferons, pegylated derivatizedinterferon-α compounds, and thymosin; other anti-viral agents, such asribavirin, amantadine, and telbivudine; other inhibitors of hepatitis Cproteases (NS2-NS3 inhibitors and NS3-NS4A inhibitors); inhibitors ofother targets in the HCV life cycle, including helicase and polymeraseinhibitors; inhibitors of internal ribosome entry; broad-spectrum viralinhibitors, such as IMPDH inhibitors (e.g., compounds of U.S. Pat. Nos.5,807,876, 6,498,178, 6,344,465, 6,054,472, WO 97/40028, WO 98/40381, WO00/56331, and mycophenolic acid and derivatives thereof, and including,but not limited to VX-497, VX-148, and/or VX-944); or combinations ofany of the above. See also W. Markland et al., Antimicrobial & AntiviralChemotherapy, 44, p. 859 (2000) and U.S. Pat. No. 6,541,496.

The following definitions are used herein (with trademarks referring toproducts available as of this application's filing date).

“Peg-Intron” means PEG-Intron®, peginteferon alfa-2b, available fromSchering Corporation, Kenilworth, N.J.;

-   -   “Intron” means Intron-A®, interferon alfa-2b available from        Schering Corporation, Kenilworth, N.J.;    -   “ribavirin” means ribavirin        (1-beta-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide,        available from ICN Pharmaceuticals, Inc., Costa Mesa, Calif.;        described in the Merck Index, entry 8365, Twelfth Edition; also        available as Rebetol® from Schering Corporation, Kenilworth,        N.J., or as Copegus® from Hoffmann-La Roche, Nutley, N.J.;    -   “Pagasys” means Pegasys®, peginterferon alfa-2a available        Hoffmann-La Roche, Nutley, N.J.;    -   “Roferon” mean Roferon®, recombinant interferon alfa-2a        available from Hoffmann-La Roche, Nutley, N.J.;    -   “Berefor” means Berefor®, interferon alfa 2 available from        Boehringer Ingelheim Pharmaceutical, Inc., Ridgefield, Conn.;    -   Sumiferon®, a purified blend of natural alpha interferons such        as Sumiferon available from Sumitomo, Japan;    -   Wellferon®, interferon alpha n1 available from Glaxo_Wellcome        LTd., Great Britain;    -   Alferon®, a mixture of natural alpha interferons made by        Interferon Sciences, and available from Purdue Frederick Co.,        CT;

The term “interferon” as used herein means a member of a family ofhighly homologous species-specific proteins that inhibit viralreplication and cellular proliferation, and modulate immune response,such as interferon alpha, interferon beta, or interferon gamma. TheMerck Index, entry 5015, Twelfth Edition.

According to one embodiment of the present invention, the interferon isα-interferon. According to another embodiment, a therapeutic combinationof the present invention utilizes natural alpha interferon 2a. Or, thetherapeutic combination of the present invention utilizes natural alphainterferon 2b. In another embodiment, the therapeutic combination of thepresent invention utilizes recombinant alpha interferon 2a or 2b. In yetanother embodiment, the interferon is pegylated alpha interferon 2a or2b. Interferons suitable for the present invention include:

-   -   (a) Intron (interferon-alpha 2B, Schering Plough),    -   (b) Peg-Intron,    -   (c) Pegasys,    -   (d) Roferon,    -   (e) Berofor,    -   (f) Sumiferon,    -   (g) Wellferon,    -   (h) consensus alpha interferon available from Amgen, Inc.,        Newbury Park, Calif.,    -   (i) Alferon;    -   (j) Viraferon®;    -   (k) Infergen®.

As is recognized by skilled practitioners, a protease inhibitor would bepreferably administered orally. Interferon is not typically administeredorally. Nevertheless, nothing herein limits the methods or combinationsof this invention to any specific dosage forms or regime. Thus, eachcomponent of a combination according to this invention may beadministered separately, together, or in any combination thereof.

In one embodiment, the protease inhibitor and interferon areadministered in separate dosage forms. In one embodiment, any additionalagent is administered as part of a single dosage form with the proteaseinhibitor or as a separate dosage form. As this invention involves acombination of compounds, the specific amounts of each compound may bedependent on the specific amounts of each other compound in thecombination. As recognized by skilled practitioners, dosages ofinterferon are typically measured in IU (e.g., about 4 million IU toabout 12 million IU).

Accordingly, agents (whether acting as an immunomodulatory agent orotherwise) that may be used in combination with a compound of thisinvention include, but are not limited to, interferon-alph 2B (Intron A,Schering Plough); Rebatron (Schering Plough, Inteferon-alpha2B+Ribavirin); pegylated interferon alpha (Reddy, K. R. et al. “Efficacyand Safety of Pegylated (40-kd) interferon alpha-2a compared withinterferon alpha-2a in noncirrhotic patients with chronic hepatitis C(Hepatology, 33, pp. 433-438 (2001); consensus interferon (Kao, J. H.,et al., “Efficacy of Consensus Interferon in the Treatement of ChronicHepatitis” J. Gastroenterol. Hepatol. 15, pp. 1418-1423 (2000),interferon-alpha 2A (Roferon A; Roche), lymphoblastoid or “natural”interferon; interferon tau (Clayette, P. et al., “IFN-tau, A NewInterferon Type I with Antiretroviral activity” Pathol. Biol. (Paris)47, pp. 553-559 (1999); interleukin 2 (Davis, G. L. et al., “FutureOptions for the Management of Hepatitis C.” Seminars in Liver Disease,19, pp. 103-112 (1999); Interleukin 6 (Davis et al. “Future Options forthe Management of Hepatitis C.” Seminars in Liver Disease 19, pp.103-112 (1999); interleukin 12 (Davis, G. L. et al., “Future Options forthe Management of Hepatitis C.” Seminars in Liver Disease, 19, pp.103-112 (1999); Ribavirin; and compounds that enhance the development oftype 1 helper T cell response (Davis et al., “Future Options for theManagement of Hepatitis C.” Seminars in Liver Disease, 19, pp. 103-112(1999). Interferons may ameliorate viral infections by exerting directantiviral effects and/or by modifying the immune response to infection.The antiviral effects of interferons are often mediated throughinhibition of viral penetration or uncoating, synthesis of viral RNA,translation of viral proteins, and/or viral assembly and release.

Compounds that stimulate the synthesis of interferon in cells(Tazulakhova, E. B. et al., “Russian Experience in Screening, analysis,and Clinical Application of Novel Interferon Inducers” J. InterferonCytokine Res., 21 pp. 65-73) include, but are not limited to, doublestranded RNA, alone or in combination with tobramycin, and Imiquimod (3MPharmaceuticals; Sauder, D. N. “Immunomodulatory and PharmacologicProperties of Imiquimod” J. Am. Acad. Dermatol., 43 pp. S6-11 (2000).

Other non-immunomodulatory or immunomodulatory compounds may be used incombination with a compound of this invention including, but not limitedto, those specified in WO 02/18369, which is incorporated herein byreference (see, e.g., page 273, lines 9-22 and page 274, line 4 to page276, line 11).

This invention may also involve administering a cytochrome P450monooxygenase inhibitor. CYP inhibitors may be useful in increasingliver concentrations and/or increasing blood levels of compounds thatare inhibited by CYP.

If an embodiment of this invention involves a CYP inhibitor, any CYPinhibitor that improves the pharmacokinetics of the relevant NS3/4Aprotease may be used in a method of this invention. These CYP inhibitorsinclude, but are not limited to, ritonavir (WO 94/14436), ketoconazole,troleandomycin, 4-methylpyrazole, cyclosporin, clomethiazole,cimetidine, itraconazole, fluconazole, miconazole, fluvoxamine,fluoxetine, nefazodone, sertraline, indinavir, nelfinavir, amprenavir,fosamprenavir, saquinavir, lopinavir, delavirdine, erythromycin, VX-944,and VX-497. Preferred CYP inhibitors include ritonavir, ketoconazole,troleandomycin, 4-methylpyrazole, cyclosporin, and clomethiazole. Forpreferred dosage forms of ritonavir, see U.S. Pat. No. 6,037,157, andthe documents cited therein: U.S. Pat. No. 5,484,801, U.S. applicationSer. No. 08/402,690, and International Applications WO 95/07696 and WO95/09614).

Methods for measuring the ability of a compound to inhibit cytochromeP50 monooxygenase activity are known (see U.S. Pat. No. 6,037,157 andYun, et al. Drug Metabolism & Disposition, vol. 21, pp. 403-407 (1993).

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level, treatment should cease.Patients may, however, require intermittent treatment on a long-termbasis upon any recurrence of disease symptoms.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of active ingredients will also depend upon the particulardescribed compound and the presence or absence and the nature of theadditional anti-viral agent in the composition.

According to another embodiment, the invention provides a method fortreating a patient infected with a virus characterized by a virallyencoded serine protease that is necessary for the life cycle of thevirus by administering to said patient a pharmaceutically acceptablecomposition of this invention. In another embodiment the methods of thisinvention are used to treat a patient suffering from a HCV infection.Such treatment may completely eradicate the viral infection or reducethe severity thereof. In one embodiment, the patient is a human being.

In an alternate embodiment, the methods of this invention additionallycomprise the step of administering to said patient an anti-viral agentpreferably an anti-HCV agent. Such anti-viral agents include, but arenot limited to, immunomodulatory agents, such as α-, β-, andγ-interferons, pegylated derivatized interferon-α compounds, andthymosin; other anti-viral agents, such as ribavirin, amantadine, andtelbivudine; other inhibitors of hepatitis C proteases (NS2-NS3inhibitors and NS3-NS4A inhibitors); inhibitors of other targets in theHCV life cycle, including helicase and polymerase inhibitors; inhibitorsof internal ribosome entry; broad-spectrum viral inhibitors, such asIMPDH inhibitors (e.g., VX-497 and other IMPDH inhibitors disclosed inU.S. Pat. Nos. 5,807,876 and 6,498,178, mycophenolic acid andderivatives thereof); inhibitors of cytochrome P-450, such as ritonavir,or combinations of any of the above.

Such additional agent may be administered to said patient as part of asingle dosage form comprising both a compound of this invention and anadditional anti-viral agent. Alternatively the additional agent may beadministered separately from the compound of this invention, as part ofa multiple dosage form, wherein said additional agent is administeredprior to, together with or following a composition comprising a compoundof this invention.

In yet another embodiment the present invention provides a method ofpre-treating a biological substance intended for administration to apatient comprising the step of contacting said biological substance witha pharmaceutically acceptable composition comprising a compound of thisinvention. Such biological substances include, but are not limited to,blood and components thereof such as plasma, platelets, subpopulationsof blood cells and the like; organs such as kidney, liver, heart, lung,etc; sperm and ova; bone marrow and components thereof, and other fluidsto be infused into a patient such as saline, dextrose, etc.

According to another embodiment the invention provides methods oftreating materials that may potentially come into contact with a viruscharacterized by a virally encoded serine protease necessary for itslife cycle. This method comprises the step of contacting said materialwith a compound according to the invention. Such materials include, butare not limited to, surgical instruments and garments (e.g. clothes,gloves, aprons, gowns, masks, eyeglasses, footwear, etc.); laboratoryinstruments and garments (e.g. clothes, gloves, aprons, gowns, masks,eyeglasses, footwear, etc.); blood collection apparatuses and materials;and invasive devices, such as shunts, stents, etc.

In another embodiment, the compounds of this invention may be used aslaboratory tools to aid in the isolation of a virally encoded serineprotease. This method comprises the steps of providing a compound ofthis invention attached to a solid support; contacting said solidsupport with a sample containing a viral serine protease underconditions that cause said protease to bind to said solid support; andeluting said serine protease from said solid support. Preferably, theviral serine protease isolated by this method is HCV NS3-NS4A protease.

In order that this invention be more fully understood, the followingpreparative and testing examples are set forth. These examples are forthe purpose of illustration only and are not to be construed as limitingthe scope of the invention in any way.

EXAMPLES

¹H-NMR spectra were recorded at 500 MHz using a Bruker AMX 500instrument. Mass spec. samples were analyzed on a MicroMass ZQ orQuattro II mass spectrometer operated in single MS mode withelectrospray ionization. Samples were introduced into the massspectrometer using flow injection (FIA) or chromatography. Mobile phasefor all mass spec. analysis consisted of acetonitrile-water mixtureswith 0.2% formic acid as a modifier.

As used herein, the term “R_(t)(min)” refers to the HPLC retention time,in minutes, associated with the compound. The HPLC retention timeslisted were either obtained from the mass spec. data or using thefollowing method:

-   Instrument: Hewlett Packard HP-1050;-   Column: YMC C₁₈ (Cat. No. 326289C46);-   Gradient/Gradient Time: 10-90% CH₃CN/H₂O over 9 minutes, then 100%    CH₃CN for 2 minutes;-   Flow Rate: 0.8 ml/min;-   Detector Wavelength: 215 nM and 245 nM.

Chemical naming for selected compounds herein was accomplished using thenaming program provided by CambridgeSoft Corporations ChemDraw Ultra®,version 7.0.1.

Example 1

N-Phenyl Oxalamic Acid (84)

Ethyl oxanilate 83 (Aldrich, 1.0 g, 1.0 eq) in 12 mL of THF was treateddropwise with a 1N NaOH solution (5.70 mL, 1.1 eq) resulting in a whiteprecipitate. After stirring for 3 hours at RT, 0.5N HCl and ethylacetate were added, the organic layer separated, washed with 0.5N HCland brine and then dried over sodium sulfate, filtered, and concentratedto give 712 mg (68%) of N-phenyl oxalamic acid 84 as a white solid withconsistent analytical data. FIA M+H=166.0, M−H=163.9; ¹H NMR (DMSO-d₆) δ10.70 (s,1H), 7.75 (m,2H), 7.35 (m,2H), 7.15 (m,1H) ppm.

Example 2N-(Cyclohexyl-{1-[2-(1-cyclopropylaminooxalyl-butylcarbamoyl)-octahydro-indole-1-carbonyl]-2,2-dimethyl-propylcarbamoyl}-N′-phenyl-oxalamide(1)

Octahydro-indole-1,2-dicarboxylic acid 1-tert-butyl ester 89 (Bachem,1.6 g, 1.0 eq) in DMF (20 mL) was treated with PyBOP (3.41 g, 1.1 eq)and NMM (1.97 mL, 3.0 eq). To this was added 3-amino-2-hydroxy-hexanoicacid cyclopropylamide 90 (1.22 g, 1.1 eq, prepared according to theprocedure of U. Schoellkogf et al., Justus Liebigs Ann. Chem. GE, pp.183-202 (1976) and J. Semple et al., Org. Letters, 2, pp. 2769-2772(2000) and NMM (1.97 mL, 3.0 eq) in DMF (3 mL) and the mixture stirredat rt overnight. The mixture was evaporated in vacuo, diluted with ethylacetate, the organic phase washed with 0.5N HCl, sodium bicarbonate andbrine, then dried over sodium sulfate, filtered and concentrated invacuo to give2-[1-cyclopropylcarbamoyl-hydroxy-methyl)-butylcarbamoyl]-octahydro-indole-1-carboxylicacid tert-butyl ester 91 which was used without further purification. ¹HNMR (CDCl₃) δ 6.92 (bs, 1H), 6.80 (bs, 1H), 3.80-4.20 (m, 3H), 2.75 (m,1H), 2.25 (m, 1H), 2.10 (m, 1H), 1.90-2.00 (m, 2H), 1.5-1.75 (m, 7H),1.45 (s, 9H), 1.10-1.40 (m, 5H), 0.90 (m, 3H), 0.75 (m, 2H), 0.50 (m,2H) ppm.

Crude Boc amide 91 was stirred in ethyl acetate (0.5N), treated withanhydrous 2N HCl in EtOAc and the mixture stirred for 2 hours. Themixture was concentrated in vacuo to give octahydro-indole-2-carboxylicacid [1-(cyclopropylcarbamoyl-hydroxy-methyl)butyl]-amide 92 which wasused without further purification. ¹H NMR (CDCl₃) δ 7.10 (bs, 1H), 6.95(bs, 1H), 4.60 (m, 1H), 4.30 (m, 1H), 3.85 (m, 1H), 2.75 (m, 1H), 2.50(m, 2H), 2.05 (m, 2H), 1.30-1.80 (m, 12H), 0.90 (m, 3H), 0.80 (m, 2H),0.60 (m, 2H) ppm.

CBz tert-butyl glycine (1.74 g, 1.1 eq), and crude amine 92 (2.01 g, 1.0eq) in DMF (20 mL) were treated with PyBOP (3.41 g, 1.1 eq) and NMM(3.93 mL, 6.0 eq) and the mixture stirred overnight at room temperature.The reaction mixture was concentrated in vacuo, diluted with EtOAc andthe organic layer washed with 0.5N HCl, brine, sodium bicarbonatesolution and brine, then dried over sodium sulfate, filtered, andconcentrated in vacuo. Purification on Merck silica gel eluting with agradient (20% EtOAc/Hexanes to 100% EtOAc) afforded 2.295 g (66%) of(1-{2-[1-(cyclopropylcarbamoyl-hydroxy-methyl)-butylcarbamoyl]-octahydro-indole-1-carbonyl}-2,2-dimethyl-propyl)-carbamicacid benzyl ester 93 as an oil with consistent analytical data. LCMS rettime=4.09 min, M+H=585.28, M−H=583.25; ¹H NMR (CDCl₃) δ 7.32 (m, 5H),6.99 (d, 1H), 6.85 (m, 1H), 5.42 (d, 1H), 5.02-5.12 (m, 2H), 4.50 (t,1H), 4.25 (d, 1H), 4.09 (m, 1H), 3.95 (m, 1H), 2.72 (m, 1H), 2.12-2.30(m, 2H), 1.95 (m, 2H), 1.59-1.81 (m, 6H), 1.50 (m, 2H), 1.22-1.42 (m,4H), 1.00 (s, 9H), 0.90 (m, 3H), 0.75 (m, 2H), 0.55 (m, 2H) ppm.

Amide 93 (1.10 g, 1.0 eq) in EtOH (10 mL) was treated with 10% Pd/C (100mg) and hydrogen gas was bubbled into the black suspension untilstarting material was consumed (monitored by TLC). Catalyst was removedby filtration and the filtrate concentrated in vacuo to give 852 mg(100% yield) of1-(2-amino-3,3-dimethyl-butyryl)-octahydro-indole-2-carboxylic acid[1-(cyclopropylcarbamoyl-hydroxy-methyl)-butyl]-amide 94 as a whitesolid with consistent NMR data. ¹H NMR (CDCl₃) δ 4.40 (m, 1H), 4.20 (m,1H), 4.10 (d, 1H), 3.95 (m, 1H), 2.70 (m, 1H), 2.40 (m, 2H), 2.0 (m,2H), 1.60-1.80 (m, 6H), 1.50 (m, 2H), 1.30 (m, 3H), 1.20 (m, 1H), 1.00(s, 9H), 0.90 (m, 3H), 0.75 (m, 2H), 0.55 (m, 2H) ppm.

CBz-cyclohexylglycine (Bachem, 747 mg, 1.05 eq) in DMF (5 mL) wastreated with PyBOP (1.33 g, 1.05 eq) and NMM (0.8 ml, 3.0 eq). To thiswas added a solution of amine 94 (1.1 g, 1.0 eq) and NMM (0.8 mL, 3.0eq) in DMF (20 mL) and the mixture stirred at room temperature for 3hours. The reaction mixture was concentrated in vacuo, diluted withethyl acetate, the organic phase washed with 0.5N HCl, brine, saturatedsodium bicarbonate solution, and brine, then dried over sodium sulfate,filtered, and concentrated in vacuo. Purification via Merck silica geleluting with 75% EtOAc/Hexanes afforded 1.18 g (67%) of[cyclohexyl-(1-{2-[1-cyclopropylcarbamoyl-hydroxy-methyl)-butylcarbamoyl]-octahydro-indole-1-carbonyl}-2,2-dimethyl-propylcarbamoyl)methyl]-carbamicacid benzyl ester 95 as a white solid with consistent analytical data.LCMS ret time=3.65, M+H=724.22, M−H=722.20; ¹H NMR (CDCl₃) δ 7.35 (m,5H), 7.05 (m, 1H), 6.90 (m, 1H), 6.55 (m, 1H), 5.35 (dd, 1), 5.10 (m,2H), 4.35-4.55 (m, 1H), 3.95-4.25 (3H), 2.75 (m, 1H), 2.20 (m, 1H), 2.00(m, 1H), 1.65-1.80 (m, 7H), 1.55 (m, 2H), 1.05-1.45 (m, 7H), 1.00 (s,9H), 0.85-1.00 (m, 7H), 0.80 (m, 2H), 0.55 (m, 2H) ppm.

CBz carbamate 95 (1.76 g, 1.0 eq) in EtOH (12 mL). was treated with 10%Pd/C (175 mg) and hydrogen gas was bubbled through the suspension untilstarting material was consumed (monitored by TLC). Catalyst was removedby filtration and the filtrate concentrated in vacuo to give 1.43 g(100%) of intermediate oxalamide as a white solid which was used withoutfurther purification.

Acid 84 (20 mg, 1.4 eq) in CH₂Cl₂ (1 mL) was treated with PyBOP (53 mg,1.2 eq) and NMM (0.028 mL, 3.0 eq) and stirred for 5 minutes. To thiswas added a solution of oxalamide (50 mg, 1.0 eq) and NMM (0.028 mL, 3.0eq) in CH₂Cl₂ (1 mL) and the mixture stirred at room temperatureovernight. The mixture was diluted with ethyl acetate, the organic phasewashed with 0.5N HCl, brine, saturated bicarbonate solution, and brine,then dried over sodium sulfate, filtered and concentrated in vacuo.Purification by preparative HPLC yielded 24 mg (38%) ofN-[cyclohexyl-(1-{2-[1-cyclopropylcarbamoyl-hydroxy-methyl)-butylcarbamoyl]-octahydro-indole-1-carbonyl}-2,2-dimethyl-propylcarbamoyl)methyl]-N′-phenyl-oxalamide96 as a white solid with consistent analytical data. LCMS ret time=4.07,M+H=737.26, M−H=735.22.

Oxalamide 96 (24 mg, 1.0 eq) in CH₂Cl₂ (1 mL) and t-BuOH (41 uL) wastreated with Dess Martin periodinane (41 mg, 3.0 eq) and the suspensionstirred at room temp. for 3 hours. Sodium thiosulfate was added and themixture stirred for 15 minutes, then diluted with ethyl acetate, theorganic phase washed with sodium bicarbonate solution and brine, thendried over anydrous sodium sulfate and concentrated in vacuo.Purification by preparative HPLC yielded 5.5 mg (23%) ofN-(cyclohexyl-{1-[2-(1-cyclopropylaminooxalyl-butylcarbamoyl)-octahydro-indole-1-carbonyl]-2,2-dimethyl-propylcarbamoyl}-N′-phenyl-oxalamide1 as a white solid with consistent analytical data. LCMS ret time=4.51,M+H=735.23, M−H=733.39.

Example 3

HCV Replicon Cell Assay Protocol:

Cells containing hepatitis C virus (HCV) replicon were maintained inDMEM containing 10% fetal bovine serum (FBS), 0.25 mg per ml of G418,with appropriate supplements (media A).

On day 1, replicon cell monolayer was treated with a trypsin:EDTAmixture, removed, and then media A was diluted into a finalconcentration of 100,000 cells per ml wit. 10,000 cells in 100 ul wereplated into each well of a 96-well tissue culture plate, and culturedovernight in a tissue culture incubator at 37° C.

On day 2, compounds (in 100% DMSO) were serially diluted into DMEMcontaining 2% FBS, 0.5% DMSO, with appropriate supplements (media B).The final concentration of DMSO was maintained at 0.5% throughout thedilution series.

Media on the replicon cell monolayer was removed, and then media Bcontaining various concentrations of compounds was added. Media Bwithout any compound was added to other wells as no compound controls.

Cells were incubated with compound or 0.5% DMSO in media B for 48 hoursin a tissue culture incubator at 37° C. At the end of the 48-hourincubation, the media was removed, and the replicon cell monolayer waswashed once with PBS and stored at −80° C. prior to RNA extraction.

Culture plates with treated replicon cell monolayers were thawed, and afixed amount of another RNA virus, such as Bovine Viral Diarrhea Virus(BVDV) was added to cells in each well. RNA extraction reagents (such asreagents from RNeasy kits) were added to the cells immediately to avoiddegradation of RNA. Total RNA was extracted according the instruction ofmanufacturer with modification to improve extraction efficiency andconsistency. Finally, total cellular RNA, including HCV replicon RNA,was eluted and stored at −80° C. until further processing.

A Taqman real-time RT-PCR quantification assay was set up with two setsof specific primers and probe. One was for HCV and the other was forBVDV. Total RNA extractants from treated HCV replicon cells was added tothe PCR reactions for quantification of both HCV and BVDV RNA in thesame PCR well. Experimental failure was flagged and rejected based onthe level of BVDV RNA in each well. The level of HCV RNA in each wellwas calculated according to a standard curve run in the same PCR plate.The percentage of inhibition or decrease of HCV RNA level due tocompound treatment was calculated using the DMSO or no compound controlas 0% of inhibition. The IC50 (concentration at which 50% inhibition ofHCV RNA level is observed) was calculated from the titration curve ofany given compound.

Example 4

HCV Enzyme Assay Protocol:

HPLC Microbore Method for Separation of 5AB Substrate and Products

Substrate:

-   NH₂-Glu-Asp-Val-Val-(alpha)Abu-Cys-Ser-Met-Ser-Tyr-COOH

A stock solution of 20 mM 5AB (or concentration of your choice) was madein DMSO w/0.2M DTT. This was stored in aliquots at −20 C.

Buffer: 50 mM HEPES, pH 7.8; 20% glycerol; 100 mM NaCl

Total assay volume was 100 μL. X1 conc. in Reagent (μL) assay Buffer86.5 see above  5 mM KK4A 0.5  25 μM 1 M DTT 0.5   5 mM DMSO orinhibitor 2.5 2.5% v/v  50 μM tNS3 0.05  25 nM 250 μM 5AB 20  25 μM(initiate)

The buffer, KK4A, DTT, and tNS3 were combined; distributed 78 μL eachinto wells of 96 well plate. This was incubated at 30 C for ˜5-10 min.

2.5 μL of appropriate concentration of test compound was dissolved inDMSO (DMSO only for control) and added to each well. This was incubatedat room temperature for 15 min.

Initiated reaction by addition of 20 μL of 250 μM 5AB substrate (25 μMconcentration is equivalent or slightly lower than the Km for 5AB).

-   -   Incubated for 20 min at 30 C.    -   Terminated reaction by addition of 25 μL of 10% TFA    -   Transferred 120 μL aliquots to HPLC vials

Separated SMSY product from substrate and KK4A by the following method:

Microbore Separation Method:

Instrumentation: Agilent 1100

-   Degasser G1322A-   Binary pump G1312A-   Autosampler G1313A-   Column thermostated chamber G1316A-   Diode array detector G1315A    Column:-   Phenomenex Jupiter; 5 micron C18; 300 angstroms; 150×2 mm; P/O    00F-4053-BO-   Column thermostat: 40 C-   Injection volume: 100 μL-   Solvent A=HPLC grade water+0.1% TFA

Solvent B=HPLC grade acetonitrile+0.1% TFA Time Flow Max (min) % B(ml/min) press.  0  5 0.2 400 12  60 0.2 400 13 100 0.2 400 16 100 0.2400 17  5 0.2 400

-   Stop time: 17 min-   Post-run time: 10 min.

Table 1 below depicts Mass Spec., HPLC, Ki and IC₅₀ data for certaincompounds of the invention. Compounds with Ki's ranging from 0.25 μM to1 μM are designated A. Compounds with Ki's ranging from 0.1 μM to 0.25μM are designated B. Compounds with Ki's below 0.1 μM are designated C.Compounds with IC₅₀'s ranging from 0.25 μM to 1 μM are designated A.Compounds with IC₅₀'s ranging from 0.1 μM to 0.25 μM are designated B.Compounds with IC₅₀'s below 0.1 μM are designated C. TABLE 1 HPLC,Compound MS+ R_(t) (min) Ki IC₅₀  1 735.2 4.51 B A  2 749.3 4.54 B A  3755.4 4.92 B A  4 699.3 4.04 B A  5 701.3 4.15 B A  6 715.2 4.34 B A  7740.2 4.19 B A  8 741.4 4.88 B A  9 727.4 4.69 A A 10 772.3 4.30 B C 11822.1 4.80 B C 12 788.0 4.70 B C

Table 2 below depicts proton NMR data for certain compounds of theinvention. ¹H-NMR spectra were recorded at 500 MHz using a Bruker AMX500 instrument. TABLE 2 Compound ¹H-NMR(500 MHz)  1 ND  2 (CDCl₃) δ8.67(bs, 1H), 7.96(d, 1H), 7.2-7.3(m, 5H), 7.90(d, 1H), 5.30(m, 1H),4.70(m, 1H), 4.65(d, 1H), 4.60(t, 1H), 4.45(d, 0.5H), 4.40(d, 0.5H),4.28(m, 1H), 4.13(m, 1H), 2.75(m, 1H), 2.35(m, 1H), 2.05(m, 1H),1.6-1.9(m, 12H), 1.4-1.5(m, 4H), 1.12-1.39(m, 7H), 1.05(m, 1H), 0.96(s,9H), 0.85(m, 5H), 0.55(m, 2H) ppm.  3 (CDCl₃) δ 8.10(bs, 1H), 7.99(d,1H), 7.87(bs, 1H), 7.52(d, 1H), 7.09(bs, 1H), 5.35(m, 1H),4.70(m, 2H),4.60(t, 1H), 4.20(m, 1H), 3.25(m, 1H), 3.10(m, 1H), 2.80(m, 1H), 2.4(m,1H), 2.10(m, 1H), 1.90(m, 3H), 1.10-1.80(m, 26H),0.97(s, 9H),0.70-0.80(m, 11H), 0.6(m, 2H) ppm.  4 (CDCl₃) δ 8.12(bs, 1H), 7.97(d,1H), 7.71(bs, 1H), 7.22(d, 1H), 6.99(d, 1H), 5.33(m, 1H), 4.67(d, 1H),4.60(t, 1H), 4.50(t, 1H), 4.20(m, 1H), 2.83(m, 1H), 2.79(m, 1H), 2.40(m,1H), 2.11(m, 1H), 1.82-2.00(m, 5H), 1.00-1.80(m, 19H), 0.97(s, 9H),0.62-0.96(m, 10H), 0.6(m, 2H) ppm.  5 (CDCl₃) δ 7.92(d, 1H), 7.60(d,1H), 7.39(d, 1H), 7.10(bs, 1H), 7.00(d, 1H), 5.35(m, 1H), 4.65(d, 1H),4.60(t, 1H), 4.40(t, 1H), 4.20(m, 1H), 4.08(m, 1H), 2.80(m, 1H), 2.45(m,1H), 2.15(m, 1H), 1.90(m, 3H), 1.65-1.83(m, 7H), 1.48-1.60(m, 4H),1.40(m, 3H), 1.23(d, 3H), 1.20(d, 3H), 1.18-1.30(m, 4H), 1.10(m, 2H),0.97(s, 9H), 0.90(m, 4H), 0.85(m, 2H), 0.62(m, 2H) ppm.  6 (CDCl₃) δ8.15(bs, 1H), 8.00(d, 1H), 7.90(bs, 1H), 7.44(d, 1H), 7.03(bs, 1H),5.35(m, 1H), 4.70(d, 1H), 4.65(t, 1H), 4.60(t, 1H), 4.20(m, 1H), 3.25(m,1H), 3.10(m, 1H), 2.80(m, 1H), 2.40(m, 1H), 2.10(m, 1H), 1.90(m, 4H),1.00-1.80(m, 21H), 0.97(s, 9H), 0.94(d, 3H), 0.93(m, 3H), 0.92(d, 3H),0.88(d, 2H), 0.62(m, 2H) ppm.  7 (CDCl₃) δ 8.07(bs, 1H), 7.97(d, 1H),6.92(d, 1H), 6.79(s, 1H), 5.22(m, 1H), 4.75(t, 1H), 4.62(d, 1H), 4.58(m,1H), 4.05(m, 1H), 2.78(m, 1H), 2.57(m, 1H), 2.42(s, 3H), 2.40(m, 1H),1.6-1.92(m, 12H), 1.15-1.50(m, 9H), 0.97-1.10(m, 4H), 0.96(s, 9H),0.82(d, 2H), 0.80(t, 3H), 0.61(m, 2H) ppm.  8 (CDCl₃) δ 7.92(d, 1H),7.59(d, 1H), 7.50(d, 1H), 7.18(d, 1H), 7.08(bs, 1H), 5.37(m, 1H),4.67(d, 1H), 4.66(m, 1H), 4.41(t, 1H), 4.20(m, 1H), 3.77(m, 1H), 2.78(m,1H), 2.4(m, 1H), 2.12(m, 1H), 1.90(m, 5H), 1.01-1.88(m, 27H), 0.99(s,9H), 0.92(m, 5H), 0.85(d, 2H), 0.62(m, 2H) ppm.  9 (CDCl₃) δ 7.90(d,1H), 7.45(d, 1H), 6.95(d, 1H), 6.67(d, 1H), 5.31(m, 1H), 4.60(m, 2H),4.30(t, 1H), 4.20(m, 1H), 2.80(m, 1H), 2.50(m, 1H), 2.15(m, 1H), 2.04(m,2H), 1.80-1.95(m, 4H), 1.02-1.78(m, 26H), 0.97(s, 9H), 0.92(m, 4H),0.92(d, 2H), 0.60(m, 2H) ppm. 10 (CDCl₃) δ 8.08(d, 1H), 7.87(d, 2H),7.58(bs, 1H), 7.50(dd, 1H), 7.48(bs, 1H), 7.10(bs, 1H), 6.51(d, 1H),5.60(m, 1H), 5.39(m, 1H), 4.93(m, 1H), 4.77(d, 1H), 4.52(t, 1H), 4.11(m,1H), 4.03(m, 1H), 2.80(m, 2H), 2.53(m, 1H), 2.30(m, 1H), 1.90(m, 1H),1.67(m, 5H), 1.57(m, 1H), 1.49(m, 1H), 1.40(m, 2H), 1.20(m, 2H), 1.07(m,1H), 0.95(s, 9H), 0.8-0.95(m, 9H), 0.65(m, 4H) ppm. 11 (CDCl₃) δ 8.10(d,1H), 7.83(d, 1H), 7.50(d, 1H), 7.36(m, 1H), 7.30(m, 7H), 7.00(bs, 1H),6.53(d, 1H), 5.59(m, 1H), 5.32(m, 1H), 4.78(m, 1H),4.72(d, 1H), 4.58(d,0.6H), 4.57(d, 0.4H), 4.48(m, 1H), 4.41(m, 1H), 4.09(m, 1H), 3.97(d,0.6H), 3.96(d, 0.4H), 2.79(m, 1H), 2.56(m, 1H), 2.25(m, 1H), 1.90(m,1H), 1.70(m, 5H), 1.50(m, 2H), 1.36(m, 2H), 1.20(m, 2H), 1.08(m, 1H),0.97(s, 9H), 0.8-0.91(m, 7H), 0.6(m, 2H) ppm. 12 (CDCl₃) δ 8.09(d, 1H),7.83(d, 1H), 7.70(bs, 1H), 7.50(m, 2H), 7.10(bs, 1H), 6.50(d, 1H),5.60(m, 1H), 5.39(m, 1H), 4.90(m, 1H), 4.70(d, 1H), 4.42(t, 1H), 4.10(m,1H), 3.98(m, 1H), 3.17(m, 2H), 2.80(m, 1H), 2.59(m, 1H), 2.27(m, 1H),1.91(m, 1H), 1.83(m, 1H), 1.68(m, 4H), 1.58(m, 1H), 1.50(m, 1H), 1.40(m,2H), 1.20(m, 2H), 1.10(m, 1H), 0.9-1.0(m, 21H), 0.84(d, 2H), 0.60(m, 2H)ppm.

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: R₉ and R_(9′) are independently: hydrogen-, (C1-C12)-aliphatic-, (C3-C10)-cycloalkyl- or -cycloalkenyl-, [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-, (C6-C10)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-, (C3-C10)-heterocyclyl-, (C3-C10)-heterocyclyl-(C1-C12)aliphatic-, (C5-C10)-heteroaryl-, or (C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein up to three aliphatic carbon atoms in each of R₉ and R_(9′) may be replaced by O, N, NH, S, SO, or SO₂; wherein each of R₉ and R_(9′) is independently and optionally substituted with up to 3 substituents independently selected from J; J is halogen, —OR′, —NO₂, —CN, —CF₃, —OCF₃, —R′, oxo, thioxo, ═N(R′), ═N(OR′), 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R′)₂, —SR′, —SOR′, —SO₂R′, —SO₂N(R′)₂, —SO₃R′, —C(O)R′, —C(O)C(O)R′, —C(O)C(O)OR′, —C(O)C(O)N(R′)₂, —C(O)CH₂C(O)R′, —C(S)R′, —C(S)OR′, —C(O)OR′, —OC(O)R′, —C(O)N(R′)₂, —OC(O)N(R′)₂, —C(S)N(R′)₂, —(CH₂)₀₋₂NHC(O)R′, —N(R′)N(R′)COR′, —N(R′)N(R′)C(O)OR′, —N(R′)N(R′)CON(R′)₂, —N(R′)SO₂R′, —N(R′)SO₂N(R′)₂, —N(R′)C(O)OR′, —N(R′)C(O)R′, —N(R′)C(S)R′, —N(R′)C(O)N(R′)₂, —N(R′)C(S)N(R′)₂, —N(COR′)COR′, —N(OR′)R′, —C(═NH)N(R′)₂, —C(O)N(OR′)R′, —C(═NOR′)R′, —OP(O)(OR′)₂, —P(O)(R′)₂, —P(O)(OR′)₂, or —P(O)(H)(OR′); wherein; R′ is independently selected from: hydrogen-, (C1-C12)-aliphatic-, (C3-C10)-cycloalkyl- or -cycloalkenyl-, [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-, (C6-C10)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-, (C3-C10)-heterocyclyl-, (C3-C10)-heterocyclyl-(C1-C12)aliphatic-, (C5-C10)-heteroaryl-, or (C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein up to 5 atoms in R′ are optionally and independently substituted with J; wherein two R′ groups bound to the same atom optionally form a 3- to 10-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, O, S, SO, and SO₂, wherein said ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, wherein any ring has up to 3 substituents selected independently from J; R₁₀, R_(10′), R₁₁, and R_(11′) are each independently: hydrogen-, (C1-C12)-aliphatic-, (C3-C10)-cycloalkyl- or -cycloalkenyl-, [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-, (C6-C10)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-, (C3-C10)-heterocyclyl-, (C3-C10)-heterocyclyl-(C1-C12)aliphatic-, (C5-C10)-heteroaryl-, or (C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein any ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl; wherein up to 3 aliphatic carbon atoms in each of R₁₀, R_(10′), R₁₁, and R_(11′) may be replaced by a heteroatom selected from O, NH, S, SO, or SO₂ in a chemically stable arrangement; wherein each of R₁₀, R_(10′), R₁₁, and R_(11′) is independently and optionally substituted with up to 3 substituents independently selected from J; or R₁₀ is —OR′ and R_(10′) is H; or R₁₀ and R_(10′) are both —OR′ or —SR′; or R₁₀ and R_(10′) are both fluorine; or R₁₀ and R_(10′) are taken together with the carbon atom to which they are bound to form a 5- to 7-membered saturated or partially unsaturated ring; wherein the R₁₀ and R_(10′) atoms bound to the carbon atom are independently C(H), N, NH, O, S, SO, or SO₂; wherein said ring may contain up to 4 heteroatoms independently selected from N, NH, O, S, SO, and SO₂; wherein any atom is optionally singly or multiply substituted with up to 2 substituents selected independently from J; and wherein said ring is optionally fused to a second ring selected from (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, and a (C3-C10)heterocyclyl, wherein said second ring has up to 3 substituents selected independently from J; or R₉ and R₁₀ are taken together with the ring atoms to which they are bound to form a 3- to 6-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, O, S, SO, or SO₂; wherein said ring is optionally substituted with up to 3 substituents selected independently from J; or R₁₀ and R₁₁ are taken together with the ring atoms to which they are bound to form a 3- to 6-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, O, S, SO, or SO₂; wherein said ring is optionally substituted with up to 3 substituents selected independently from J; or R₉ and R₁₁ are taken together with the ring atoms to which they are bound to form a bridged bicyclic saturated or partially unsaturated carbocyclic or heterocyclic ring system containing up to 10 atoms; wherein said ring system is optionally substituted with up to 3 substituents selected independently from J; wherein each heteroatom in the heterocyclic ring system is selected from the group consisting of N, NH, O, S, SO, or SO₂; R₁ and R₃ are independently: (C1-C12)-aliphatic-, (C3-C10)-cycloalkyl- or -cycloalkenyl-, [(C3-C10)-cycloalkyl- or -cycloalkenyl]-(C1-C12)-aliphatic-, (C6-C10)-aryl-(C1-C12)aliphatic-, or (C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein up to 3 aliphatic carbon atoms in each of R₁ and R₃ may be replaced by a heteroatom selected from O, N, NH, S, SO, or SO₂ in a chemically stable arrangement; wherein each of R₁ and R₃ is independently and optionally substituted with up to 3 substituents independently selected from J; R₂, R₄, and R₇ are each independently: hydrogen-, (C1-C12)-aliphatic-, (C3-C10)-cycloalkyl-(C1-C12)-aliphatic-, or (C6-C10)-aryl-(C1-C12)-aliphatic-; wherein up to two aliphatic carbon atoms in each of R₂, R₄, and R₇ may be replaced by a heteroatom selected from O, N, NH, S, SO, and SO₂ in a chemically stable arrangement; wherein each of R₂, R₄, and R₇ is optionally substituted with up to 3 substituents independently selected from J; R₅ and R_(5′) are independently hydrogen or (C1-C12)-aliphatic, wherein any hydrogen is optionally replaced with halogen; wherein any terminal carbon atom of R₅ is optionally substituted with sulfhydryl or hydroxy; or R₅ is Ph or —CH₂Ph and R_(5′) is H, wherein said Ph or —CH₂Ph group is optionally substituted with up to 3 substituents independently selected from J; or R₅ and R_(5′) together with the atom to which they are bound optionally form a 3- to 6-membered saturated or partially unsaturated ring having up to 2 heteroatoms selected from N, NH, O, SO, and SO₂; wherein said ring is optionally substituted with up to 2 substituents selected independently from J; W is:

wherein each R₆ is independently: hydrogen-, (C1-C12)-aliphatic-, (C6-C10)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-, (C3-C10)-cycloalkyl- or cycloalkenyl-, [(C3-C10)-cycloalkyl- or cycloalkenyl]-(C1-C12)-aliphatic-, (C3-C10)-heterocyclyl-, (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, (C5-C10)-heteroaryl-, or (C5-C10)-heteroaryl-(C1-C12)-aliphatic-, wherein R₆ is optionally substituted with up to 3 J substituents; or two R₆ groups, together with the nitrogen atom to which they are bound, optionally form a 3- to 10-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, O, S, SO, and SO₂, wherein said ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, wherein any ring has up to 3 substituents selected independently from J; wherein each R₈ is independently —OR′; or the R₈ groups together with the boron atom, optionally form a (C3-C10)-membered heterocyclic ring having in addition to the boron up to 3 additional heteroatoms selected from N, NR′, O, SO, and SO₂; X is —C(O)—, —S(O)—, or —S(O)₂—, V is —C(O)—, —S(O)—, —S(O)₂—, or —N(R₁₃)—; wherein R₁₃ is: hydrogen-, (C1-C12)-aliphatic-, (C3-C10)-cycloalkyl- or -cycloalkenyl-, [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-, (C6-C10)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-, (C3-C10)-heterocyclyl-, (C3-C10)-heterocyclyl-(C1-C12)aliphatic-, (C5-C10)-heteroaryl-, or (C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein up to two aliphatic carbon atoms in R₁₃ may be replaced by a heteroatom selected from O, N, NH, S, SO, and SO₂ in a chemically stable arrangement; wherein R₁₃ is independently and optionally substituted with up to 3 substituents independently selected from J; R₁₂ and R_(12′) are independently: hydrogen; (C1-C12)-aliphatic-; (C6-C10)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-, (C3-C10)-cycloalkyl or -cycloalkenyl-, [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-, (C3-C10)-heterocyclyl-, (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, (C5-C10)-heteroaryl-, or (C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein up to 3 aliphatic carbon atoms in each of R₁₂ or R_(12′) may be replaced by a heteroatom selected from O, N, NH, S, SO, or SO₂ in a chemically stable arrangement; wherein each of R₁₂ or R_(12′) is optionally substituted with up to 3 substituents independently selected from J; or R₁₂ and R_(12′) together with the nitrogen atom to which they are bound, form a (C3-C10)-heterocyclic ring; wherein said (C3-C10)-heterocyclic ring is optionally substituted with up to 3 substituents independently selected from J.
 2. A compound of formula I-1:

or a pharmaceutically acceptable salt thereof, wherein: z is 0 or 1; R₉ and R_(9′) are independently: hydrogen-, (C1-C12)-aliphatic-, (C3-C10)-cycloalkyl- or -cycloalkenyl-, [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-, (C6-C10)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-, (C3-C10)-heterocyclyl-, (C3-C10)-heterocyclyl-(C1-C12)aliphatic-, (C5-C10)-heteroaryl-, or (C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein up to three aliphatic carbon atoms in each of R₉ and R_(9′) may be replaced by O, N, NH, S, SO, or SO₂; wherein each of R₉ and R_(9′) is independently and optionally substituted with up to 3 substituents independently selected from J; J is halogen, —OR′, —NO₂, —CN, —CF₃, —OCF₃, —R′, oxo, thioxo, ═N(R′), ═N(OR′), 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R′)₂, —SR′, —SOR′, —SO₂R′, —SO₂N(R′)₂, —SO₃R′, —C(O)R′, —C(O)C(O)R′, —C(O)C(O)OR′, —C(O)C(O)N(R′)₂, —C(O)CH₂C(O)R′, —C(S)R′, —C(S)OR′, —C(O)OR′, —OC(O)R′, —C(O)N(R′)₂, —OC(O)N(R′)₂, —C(S)N(R′)₂, —(CH₂)₀₋₂NHC(O)R′, —N(R′)N(R′)COR′, —N(R′)N(R′)C(O)OR′, —N(R′)N(R′)CON(R′)₂, —N(R′)SO₂R′, —N(R′)SO₂N(R′)₂, —N(R′)C(O)OR′, —N(R′)C(O)R′, —N(R′)C(S)R′, —N(R′)C(O)N(R′)₂, —N(R′)C(S)N(R′)₂, —N(COR′)COR′, —N(OR′)R′, —C(═NH)N(R′)₂, —C(O)N(OR′)R′, —C(═NOR′)R′, —OP(O)(OR′)₂, —P(O)(R′)₂, —P(O)(OR′)₂, or —P(O)(H)(OR′); wherein; R′ is independently selected from: hydrogen-, (C1-C12)-aliphatic-, (C3-C10)-cycloalkyl- or -cycloalkenyl-, [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-, (C6-C10)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-, (C3-C10)-heterocyclyl-, (C3-C10)-heterocyclyl-(C1-C12)aliphatic-, (C5-C10)-heteroaryl-, or (C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein up to 5 atoms in R′ are optionally and independently substituted with J; wherein two R′ groups bound to the same atom optionally form a 3- to 10-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, O, S, SO, and SO₂, wherein said ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, wherein any ring has up to 3 substituents selected independently from J; R₁₀, R_(10′), R₁₁, and R_(11′) are each independently: hydrogen-, (C1-C12)-aliphatic-, (C3-C10)-cycloalkyl- or -cycloalkenyl-, [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-, (C6-C10)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-, (C3-C10)-heterocyclyl-, (C3-C10)-heterocyclyl-(C1-C12)aliphatic-, (C5-C10)-heteroaryl-, or (C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein any ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl; wherein up to 3 aliphatic carbon atoms in each of R₁₀, R_(10′), R₁₁, and R_(11′) may be replaced by a heteroatom selected from O, NH, S, SO, or SO₂ in a chemically stable arrangement; wherein each of R₁₀, R_(10′), R₁₁, and R_(11′) is independently and optionally substituted with up to 3 substituents independently selected from J; or R₁₀ is —OR′ and R_(10′) is H; or R₁₀ and R_(10′) are both —OR′ or —SR′; or R₁₀ and R_(10′) are both fluorine; or R₁₀ and R_(10′) are taken together with the carbon atom to which they are bound to form a 5- to 7-membered saturated or partially unsaturated ring; wherein the R₁₀ and R_(10′) atoms bound to the carbon atom are independently C(H), N, NH, O, S, SO, or SO₂; wherein said ring may contain up to 4 heteroatoms independently selected from N, NH, O, S, SO, and SO₂; wherein any atom is optionally singly or multiply substituted with up to 2 substituents selected independently from J; and wherein said ring is optionally fused to a second ring selected from (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, and a (C3-C10)heterocyclyl, wherein said second ring has up to 3 substituents selected independently from J; or R₉ and R₁₀ are taken together with the ring atoms to which they are bound to form a 3- to 6-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, O, S, SO, or SO₂; wherein said ring is optionally substituted with up to 3 substituents selected independently from J; or R₁₀ and R₁₁ are taken together with the ring atoms to which they are bound to form a 3- to 6-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, O, S, SO, or SO₂; wherein said ring is optionally substituted with up to 3 substituents selected independently from J; or R₉ and R₁₁ are taken together with the ring atoms to which they are bound to form a bridged bicyclic saturated or partially unsaturated carbocyclic or heterocyclic ring system containing up to 10 atoms; wherein said ring system is optionally substituted with up to 3 substituents selected independently from J; wherein each heteroatom in the heterocyclic ring system is selected from the group consisting of N, NH, O, S, SO, or SO₂; R₁ (if present) and R₃ are independently: (C1-C12)-aliphatic-, (C3-C10)-cycloalkyl- or -cycloalkenyl-, [(C3-C10)-cycloalkyl- or -cycloalkenyl]-(C1-C12)-aliphatic-, (C6-C10)-aryl-(C1-C12)aliphatic-, or (C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein up to 3 aliphatic carbon atoms in each of R₁ (if present) and R₃ may be replaced by a heteroatom selected from O, N, NH, S, SO, or SO₂ in a chemically stable arrangement; wherein each of R₁ (if present) and R₃ is independently and optionally substituted with up to 3 substituents independently selected from J; R₂, R₄, and R₇ (if present) are each independently: hydrogen-, (C1-C12)-aliphatic-, (C3-C10)-cycloalkyl-(C1-C12)-aliphatic-, or (C6-C10)-aryl-(C1-C12)-aliphatic-; wherein up to two aliphatic carbon atoms in each of R₂, R₄, and R₇ (if present) may be replaced by a heteroatom selected from O, N, NH, S, SO, and SO₂ in a chemically stable arrangement; wherein each of R₂, R₄, and R₇ (if present) is optionally substituted with up to 3 substituents independently selected from J; R₅ and R_(5′) are independently hydrogen or (C1-C12)-aliphatic, wherein any hydrogen is optionally replaced with halogen; wherein any terminal carbon atom of R₅ is optionally substituted with sulfhydryl or hydroxy; or R₅ is Ph or —CH₂Ph and R_(5′) is H, wherein said Ph or —CH₂Ph group is optionally substituted with up to 3 substituents independently selected from J; or R₅ and R_(5′) together with the atom to which they are bound optionally form a 3- to 6-membered saturated or partially unsaturated ring having up to 2 heteroatoms selected from N, NH, O, SO, and SO₂; wherein said ring is optionally substituted with up to 2 substituents selected independently from J; W is:

wherein Y is —CO₂H, a derivative of —CO₂H, or a bioisostere of —CO₂H; each R₆ is independently: hydrogen-, (C1-C12)-aliphatic-, (C6-C10)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-, (C3-C10)-cycloalkyl- or cycloalkenyl-, [(C3-C10)-cycloalkyl- or cycloalkenyl]-(C1-C12)-aliphatic-, (C3-C10)-heterocyclyl-, (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, (C5-C10)-heteroaryl-, or (C5-C10)-heteroaryl-(C1-C12)-aliphatic-, wherein R₆ is optionally substituted with up to 3 J substituents; or two R₆ groups, together with the nitrogen atom to which they are bound, optionally form a 3- to 10-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, O, S, SO, and SO₂, wherein said ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, wherein any ring has up to 3 substituents selected independently from J; wherein each R₈ is independently —OR′; or the R₈ groups together with the boron atom, optionally form a (C3-C10)-membered heterocyclic ring having in addition to the boron up to 3 additional heteroatoms selected from N, NR′, O, SO, and SO₂; X is —C(O)—, —S(O)—, or —S(O)₂—, V is —C(O)-*, —S(O)—, —S(O)₂—, or —N(R₁₃)—; wherein R₁₃ is: hydrogen-, (C1-C12)-aliphatic-, (C3-C10)-cycloalkyl- or -cycloalkenyl-, [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-, (C6-C10)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-, (C3-C10)-heterocyclyl-, (C3-C10)-heterocyclyl-(C1-C12)aliphatic-, (C5-C10)-heteroaryl-, or (C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein up to two aliphatic carbon atoms in R₁₃ may be replaced by a heteroatom selected from O, N, NH, S, SO, and SO₂ in a chemically stable arrangement; wherein R₁₃ is independently and optionally substituted with up to 3 substituents independently selected from J; R₁₂ and R₁₂, are independently: hydrogen; (C1-C12)-aliphatic-; (C6-C10)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-, (C3-C10)-cycloalkyl or -cycloalkenyl-, [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-, (C3-C10)-heterocyclyl-, (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, (C5-C10)-heteroaryl-, or (C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein up to 3 aliphatic carbon atoms in each of R₁₂ or R_(12′) may be replaced by a heteroatom selected from O, N, NH, S, SO, or SO₂ in a chemically stable arrangement; wherein each of R₁₂ or R_(12′) is optionally substituted with up to 3 substituents independently selected from J; or R₁₂ and R_(12′) together with the nitrogen atom to which they are bound, form a (C3-C10)-heterocyclic ring; wherein said (C3-C10)-heterocyclic ring is optionally substituted with up to 3 substituents independently selected from J; and R₁₄ and R₁₅ are independently: (C1-C12)-aliphatic-, (C3-C10)-cycloalkyl- or -cycloalkenyl-, [(C3-C10)-cycloalkyl- or -cycloalkenyl]-(C1-C12)-aliphatic-, (C6-C10)-aryl-(C1-C12)aliphatic-, (C5-C10)-heteroaryl-(C1-C12)aliphatic-, wherein up to 3 aliphatic carbon atoms in R₁₄ and R₁₅ may be replaced by a heteroatom selected from O, N, NH, S, SO, or SO₂ in a chemically stable arrangement; wherein each of R₁₄ and R₁₅ is independently and optionally substituted at each substitutable position with up to 3 substituents independently selected from J.
 3. The compound according to claim 1 or claim 2, wherein the

radical is:

wherein: R₁₂, R_(12′), and R₁₃ are as defined in claim 1 or claim
 2. 4. The compound according to claim 3, wherein the in the

radical; R_(12′) is hydrogen; R₁₂ is: (C1-C12)-aliphatic-; (C6-C10)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-, (C3-C10)-cycloalkyl or -cycloalkenyl-, [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-, (C3-C10)-heterocyclyl-, (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, (C5-C10)-heteroaryl-, or (C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein up to 3 aliphatic carbon atoms in R₁₂ may be replaced by a heteroatom selected from O, N, NH, S, SO, or SO₂ in a chemically stable arrangement; and wherein R₁₂ is optionally substituted with up to 3 substituents independently selected from J; and R₁₃ is as defined in claim 1 or claim
 2. 5. The compound according to claim 4, wherein; R₁₂ is: (C1-C12)-aliphatic-; (C6-C10)-aryl-(C1-C12)aliphatic-, or (C3-C10)-cycloalkyl or -cycloalkenyl-; wherein up to 3 aliphatic carbon atoms in R₁₂ may be replaced by a heteroatom selected from O, N, NH, S, SO, or SO₂ in a chemically stable arrangement; and wherein R₁₂ is optionally substituted with up to 3 substituents independently selected from J; and R₁₃ is as defined in claim 1 or claim
 2. 6. The compound according to claim 5, wherein the radical is:


7. The compound according to claim 6, wherein the

radical is:


8. The compound according to claim 1 or claim 2, wherein the

radical is:

wherein: R₁₂, R_(12′), and R₁₃ are as defined in claim 1 or claim
 2. 9. The compound according to claim 8, wherein: R_(12′) is hydrogen; and R₁₂ is: (C1-C12)-aliphatic-; (C6-C10)-aryl-(C1-C12)aliphatic-, or (C3-C10)-cycloalkyl or -cycloalkenyl-; wherein up to 3 aliphatic carbon atoms in R₁₂ may be replaced by a heteroatom selected from O, N, NH, S, SO, or SO₂ in a chemically stable arrangement; and wherein R₁₂ is optionally substituted with up to 3 substituents independently selected from J.
 10. The compound according to any one of claims 1-9, wherein the

radical is:

wherein: n is 0, 1, or 2; Z and Z′ are independently C(H), N, NH, O, or S; R₉, R_(9′), R₁₁, and R_(11′) are as defined in claim 1; and the spirocyclic ring containing Z and Z′ is optionally substituted with up to 3 J substituents, wherein J is as defined in claim
 1. 11. The compound according to claim 10, wherein the radical is:

wherein: R₉, R_(9′), R₁₁, and R_(11′) are H; and n is 0, 1, or
 2. 12. The compound according to claim 11, wherein the

radical is:

wherein: n is 0 or
 1. 13. The compound according to any one of claims 1-9, wherein the

radical is:

wherein: R′ is: (C6-C10)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-, (C3-C10)-heterocyclyl-, (C3-C10)-heterocyclyl-(C1-C12)aliphatic-, (C5-C10)-heteroaryl-, or (C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein up to 5 atoms in R′ are optionally and independently substituted with J; and R₉, R_(9′), R_(10′), R₁₁, and R_(11′) are as defined in claim
 1. 14. The compound according to claim 13, wherein the

radical is:

wherein the R′ ring is optionally substituted with up to 5 substituents independently selected from J.
 15. The compound according to claim 14, wherein the radical is:


16. The compound according to any one of claims 1-9, wherein the

radical is:

wherein: R′ is selected from: (C6-C10)-aryl-(C1-C12) aliphatic-, (C3-C10)-heterocyclyl-(C1-C12)aliphatic-, and (C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein up to 5 atoms in R′ are optionally and independently substituted with J; and R₉, R_(9′), R_(10′), R₁₁, and R_(11′) are as defined in claim
 1. 17. The compound according to claim 16, wherein the

radical is:

wherein up to 5 atoms in R′ are optionally and independently substituted with J.
 18. The compound according to anyone of claims 1-9, wherein in the

radical; R₉, R₁₀, R_(10′), R₁₁, and R_(11′) are as defined in claim 1; and R_(9′) is: (C1-C12)-aliphatic-, (C3-C10)-cycloalkyl- or -cycloalkenyl-, (C6-C10)-aryl-, (C3-C10)-heterocyclyl-, or (C5-C10)-heteroaryl-; wherein up to three aliphatic carbon atoms in R_(9′) may be replaced by O, N, NH, S, SO, or SO₂; and wherein R_(9′) is independently and optionally substituted with up to 3 substituents independently selected from J.
 19. The compound according to claim 18, wherein the radical is:

wherein R_(9′) is independently and optionally substituted with up to 3 substituents independently selected from J.
 20. The compound according to any one of claims 1-9, wherein in the

radical; R₉, R_(9′), R₁₀, R₁₁, and R_(11′) are H; and R_(10′) is: (C1-C12)-aliphatic-, (C3-C10)-cycloalkyl- or -cycloalkenyl-, (C6-C10)-aryl-, wherein any ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl; wherein up to 3 aliphatic carbon atoms in R_(10′) may be replaced by a heteroatom selected from O, NH, S, SO, or SO₂ in a chemically stable arrangement; and wherein R_(10′), is independently and optionally substituted with up to 3 substituents independently selected from J.
 21. The compound according to claim 20, wherein the radical is:

wherein the R_(10′) group, is independently and optionally substituted with up to 3 substituents independently selected from J.
 22. The compound according to any one of claims 1-9, wherein in the

radical, R₉, R₁₀, R₁₁, and R_(11′) are H; and R_(9′) and R_(10′) are: (C1-C12)-aliphatic-, (C3-C10)-cycloalkyl- or -cycloalkenyl-, wherein up to 3 aliphatic carbon atoms in R_(9′) and R_(10′) may be replaced by a heteroatom selected from O, NH, S, SO, or SO₂ in a chemically stable arrangement; and wherein R_(9′) and R_(10′) are independently and optionally substituted with up to 3 substituents independently selected from J.
 23. The compound according to claim 22, wherein the radical is:


24. The compound according to any one of claims 1-9, wherein the

radical is:

wherein; ring A is a 5- to 6-membered aromatic or a 3- to 6-membered non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, O, SO, or SO₂; wherein said ring A is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl; wherein any ring has up to 3 substituents selected independently from J; and R₉, R_(9′), R_(10′), and R_(11′) are as defined in claim
 1. 25. The compound according to claim 24, wherein the radical is:

wherein any ring has up to 3 substituents selected independently from J.
 26. The compound according to claim 25, wherein the radical is:

wherein any ring has up to 3 substituents selected independently from J.
 27. The compound according to claim 26, wherein the radical is:


28. The compound according to any one of claims 1-9, wherein the

radical is:

wherein: ring B forms a 3- to a 20-membered carbocyclic or heterocyclic ring system; wherein each ring B is either aromatic or nonaromatic; wherein each heteroatom in the heterocyclic ring system is N, NH, O, SO, or SO₂; wherein ring B is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl; wherein each ring has up to 3 substituents selected independently from J; and R_(9′) and R_(11′) are as defined in claim
 1. 29. The compound according to claim 28, wherein the

radical is:


30. The compound according to any one of claims 1-29, wherein W is:

wherein in the W, the NR₆R₆ is selected from —NH—(C1-C6 aliphatic), —NH—(C3-C6 cycloalkyl), —NH—CH(CH₃)-aryl, or —NH—CH(CH₃)-heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with up to 3 halogens.
 31. The compound according to claim 30, wherein in the W, the NR₆R₆ is:


32. The compound according to claim 31, wherein in the W, the NR₆R₆ is:


33. The compound according to claim 32, wherein in the W, the NR₆R₆ is:


34. The compound according to claim 33, wherein in the W, the NR₆R₆ is:


35. The compound according to any one of claims 1-34, wherein R_(5′) is hydrogen and R₅ is:


36. The compound according to claim 35, wherein R_(5′) is hydrogen and R₅ is:


37. The compound according to any one of claims 1-36, wherein R₂, R₄, R₇, and R_(12′), if present, are each independently H, methyl, ethyl, or propyl.
 38. The compound according to claim 37, wherein R₂, R₄, R₇, and R_(12′), if present, are each H.
 39. The compound according to any one of claims 1-38, wherein R₃ is:


40. The compound according to claim 39, wherein R₃ is:


41. The compound according to claim 40, wherein R³ is:


42. The compound according to any one of claims 1-41, wherein R¹, if present, is:


43. The compound according to claim 42, wherein R₁, if present, is:


44. The compound according to claim 43, wherein R₁, if present, is cyclohexyl.
 45. The compound according to claim 1, wherein the compound is:


46. A pharmaceutical composition comprising a compound according to any one of claims 1-45, or a pharmaceutically acceptable salt thereof in an amount effective to inhibit a serine protease; and a acceptable carrier, adjuvant or vehicle.
 47. The composition according to claim 46, wherein said composition is formulated for administration to a patient.
 48. The composition according to claim 47, wherein said composition comprises an additional agent selected from an immunomodulatory agent; an antiviral agent; a second inhibitor of HCV protease; an inhibitor of another target in the HCV life cycle; and a cytochrome P-450 inhibitor; or combinations thereof.
 49. The composition according to claim 48, wherein said immunomodulatory agent is α-, β-, or γ-interferon or thymosin; said antiviral agent is ribavirin, amantadine, or telbivudine; or said inhibitor of another target in the HCV life cycle is an inhibitor of HCV helicase, polymerase, or metalloprotease.
 50. The composition according to claim 48, wherein said cytochrome P-450 inhibitor is ritonavir.
 51. A method of inhibiting the activity of a serine protease comprising the step of contacting said serine protease with a compound according to any one of claims 1-45.
 52. The method according to claim 51, wherein said protease is an HCV NS3 protease.
 53. A method of treating an HCV infection in a patient comprising the step of administering to said patient a composition according to claim
 47. 54. The method according to claim 53, comprising administering to said patient an additional agent selected from an immunomodulatory agent; an antiviral agent; a second inhibitor of HCV protease; an inhibitor of another target in the HCV life cycle; or combinations thereof; wherein said additional agent is administered to said patient as part of said composition according to claim 47 or as a separate dosage form.
 55. The method according to claim 54, wherein said immunomodulatory agent is α-, β-, or γ-interferon or thymosin; said antiviral agent is ribavarin or amantadine; or said inhibitor of another target in the HCV life cycle is an inhibitor of HCV helicase, polymerase, or metalloprotease.
 56. A method of eliminating or reducing HCV contamination of a biological sample or medical or laboratory equipment, comprising the step of contacting said biological sample or medical or laboratory equipment with a composition according to claim
 46. 57. The method according to claim 56, wherein said sample or equipment is selected from blood, other body fluids, biological tissue, a surgical instrument, a surgical garment, a laboratory instrument, a laboratory garment, a blood or other body fluid collection apparatus; a blood or other body fluid storage material.
 58. The method according to claim 57, wherein said body fluid is blood.
 59. A process for preparing a compound of formula I, as defined in claim 1, or a compound of formula I-1 as defined in claim 2, comprising the step of: reacting a compound of formula VII in the presence of a compound of formula VIII to provide a compound of formula IX:

wherein: R₁₇ is an amine protecting group, a P3-residue of an HCV protease inhibitor described herein, or a P4-P3-residue of an HCV protease inhibitor as described herein, and wherein the P3 and the P4-P3 residues are optionally substituted with an amino-terminal capping group; R₁₇ is a carboxy protecting group or a P1 residue of an HCV protease inhibitor described herein, wherein the P1 residue is optionally substituted with a carboxy terminal protecting group or with W; R′ is as defined in claim 1; and X is an appropriate leaving group. 